Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—α: Potential Cause for Mucoid Otitis Media
Identifieur interne : 001552 ( Istex/Corpus ); précédent : 001551; suivant : 001553Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—α: Potential Cause for Mucoid Otitis Media
Auteurs : Jizhen Lin ; Atsushi Haruta ; Hirokazu Kawano ; Samuel B. Ho ; George L. Adams ; Steven K. Juhn ; Youngki KimSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2000.
Abstract
Mucoid otitis media (MOM) is characterized by viscous fluid, high in mucin concentration, which accumulates in the middle ear cavity. Recent studies suggest that initial infection in the middle ear cleft may be key to the development of MOM. However, factors of the initial infection attributed to the stimulation of mucin production are not clearly understood. This study demonstrated that tumor necrosis factor (TNF)—α, a proinflammatory cytokine in mucoid effusion, markedly increased Muc2 mucin mRNA expression in middle ear epithelium, in a time- and dose-dependent manner. Parallel to this was a marked increase in mucin glycoprotein in middle ear fluid. Also, TNF-α demonstrated an autocrine and/or paracrine effect on the expression of endogenous TNF-α gene in the middle ear, which may contribute to the production of mucin in this study. These findings suggest that TNF-α plays an important role in the development of MOM by stimulating mucin metabolism.
Url:
DOI: 10.1086/315767
Links to Exploration step
ISTEX:8834A29A576FC54DF337614048EF5CA0F08063F5Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—α: Potential Cause for Mucoid Otitis Media</title><author><name sortKey="Lin, Jizhen" sort="Lin, Jizhen" uniqKey="Lin J" first="Jizhen" last="Lin">Jizhen Lin</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: linxx004@tc.umn.edu</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Jizhen Lin, Room 216, Lions Research Bldg., 2001 6th St. SE, Minneapolis MN 55455 (linxx004@tc.umn.edu).</mods:affiliation></affiliation></author><author><name sortKey="Haruta, Atsushi" sort="Haruta, Atsushi" uniqKey="Haruta A" first="Atsushi" last="Haruta">Atsushi Haruta</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Kawano, Hirokazu" sort="Kawano, Hirokazu" uniqKey="Kawano H" first="Hirokazu" last="Kawano">Hirokazu Kawano</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Ho, Samuel B" sort="Ho, Samuel B" uniqKey="Ho S" first="Samuel B." last="Ho">Samuel B. Ho</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Medicine, Minneapolis, Minnesota</mods:affiliation></affiliation><affiliation><mods:affiliation>Otitis Media Research Center, Department of Veterans Affairs Medical Center, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Adams, George L" sort="Adams, George L" uniqKey="Adams G" first="George L." last="Adams">George L. Adams</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Juhn, Steven K" sort="Juhn, Steven K" uniqKey="Juhn S" first="Steven K." last="Juhn">Steven K. Juhn</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Kim, Youngki" sort="Kim, Youngki" uniqKey="Kim Y" first="Youngki" last="Kim">Youngki Kim</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:8834A29A576FC54DF337614048EF5CA0F08063F5</idno><date when="2000" year="2000">2000</date><idno type="doi">10.1086/315767</idno><idno type="url">https://api.istex.fr/ark:/67375/HXZ-XV76BB0D-F/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">001552</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001552</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—<hi rend="italic">α</hi>: Potential Cause for Mucoid Otitis Media</title><author><name sortKey="Lin, Jizhen" sort="Lin, Jizhen" uniqKey="Lin J" first="Jizhen" last="Lin">Jizhen Lin</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: linxx004@tc.umn.edu</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Jizhen Lin, Room 216, Lions Research Bldg., 2001 6th St. SE, Minneapolis MN 55455 (linxx004@tc.umn.edu).</mods:affiliation></affiliation></author><author><name sortKey="Haruta, Atsushi" sort="Haruta, Atsushi" uniqKey="Haruta A" first="Atsushi" last="Haruta">Atsushi Haruta</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Kawano, Hirokazu" sort="Kawano, Hirokazu" uniqKey="Kawano H" first="Hirokazu" last="Kawano">Hirokazu Kawano</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Ho, Samuel B" sort="Ho, Samuel B" uniqKey="Ho S" first="Samuel B." last="Ho">Samuel B. Ho</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Medicine, Minneapolis, Minnesota</mods:affiliation></affiliation><affiliation><mods:affiliation>Otitis Media Research Center, Department of Veterans Affairs Medical Center, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Adams, George L" sort="Adams, George L" uniqKey="Adams G" first="George L." last="Adams">George L. Adams</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Juhn, Steven K" sort="Juhn, Steven K" uniqKey="Juhn S" first="Steven K." last="Juhn">Steven K. Juhn</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</mods:affiliation></affiliation></author><author><name sortKey="Kim, Youngki" sort="Kim, Youngki" uniqKey="Kim Y" first="Youngki" last="Kim">Youngki Kim</name><affiliation><mods:affiliation>Otitis Media Research Center, Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published">2000</date><biblScope unit="vol">182</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="882">882</biblScope><biblScope unit="page" to="887">887</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Mucoid otitis media (MOM) is characterized by viscous fluid, high in mucin concentration, which accumulates in the middle ear cavity. Recent studies suggest that initial infection in the middle ear cleft may be key to the development of MOM. However, factors of the initial infection attributed to the stimulation of mucin production are not clearly understood. This study demonstrated that tumor necrosis factor (TNF)—α, a proinflammatory cytokine in mucoid effusion, markedly increased Muc2 mucin mRNA expression in middle ear epithelium, in a time- and dose-dependent manner. Parallel to this was a marked increase in mucin glycoprotein in middle ear fluid. Also, TNF-α demonstrated an autocrine and/or paracrine effect on the expression of endogenous TNF-α gene in the middle ear, which may contribute to the production of mucin in this study. These findings suggest that TNF-α plays an important role in the development of MOM by stimulating mucin metabolism.</div></front></TEI><istex><corpusName>oup</corpusName><keywords><teeft><json:string>mucin</json:string><json:string>muc2</json:string><json:string>mrna</json:string><json:string>glycoprotein</json:string><json:string>effusion</json:string><json:string>otitis</json:string><json:string>cdna</json:string><json:string>epithelial</json:string><json:string>receptor</json:string><json:string>muc3</json:string><json:string>muc1</json:string><json:string>muc5ac</json:string><json:string>muc4</json:string><json:string>tumor necrosis factor</json:string><json:string>epithelial cell</json:string><json:string>mucin mrna</json:string><json:string>quantitation</json:string><json:string>gure</json:string><json:string>inoculated</json:string><json:string>mucin glycoprotein</json:string><json:string>northern analysis</json:string><json:string>primer</json:string><json:string>mucoid</json:string><json:string>hybridizing</json:string><json:string>muc2 mrna</json:string><json:string>mucin gene</json:string><json:string>hybridizing signal</json:string><json:string>muc2 mucin gene</json:string><json:string>otitis medium</json:string><json:string>protein kinase</json:string><json:string>muc2 mucin mrna</json:string><json:string>bacterial infection</json:string><json:string>necrosis</json:string><json:string>important role</json:string><json:string>time point</json:string><json:string>negative control</json:string><json:string>control animal</json:string><json:string>eustachian tube</json:string><json:string>mucin gene expression</json:string><json:string>muc2 mucin gene expression</json:string><json:string>gene expression</json:string><json:string>gene</json:string></teeft></keywords><author><json:item><name>Jizhen Lin</name><affiliations><json:string>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</json:string><json:string>E-mail: linxx004@tc.umn.edu</json:string><json:string>Reprints or correspondence: Dr. Jizhen Lin, Room 216, Lions Research Bldg., 2001 6th St. SE, Minneapolis MN 55455 (linxx004@tc.umn.edu).</json:string></affiliations></json:item><json:item><name>Atsushi Haruta</name><affiliations><json:string>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</json:string></affiliations></json:item><json:item><name>Hirokazu Kawano</name><affiliations><json:string>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</json:string></affiliations></json:item><json:item><name>Samuel B. Ho</name><affiliations><json:string>Otitis Media Research Center, Department of Medicine, Minneapolis, Minnesota</json:string><json:string>Otitis Media Research Center, Department of Veterans Affairs Medical Center, Minneapolis, Minnesota</json:string></affiliations></json:item><json:item><name>George L. Adams</name><affiliations><json:string>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</json:string></affiliations></json:item><json:item><name>Steven K. Juhn</name><affiliations><json:string>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</json:string></affiliations></json:item><json:item><name>Youngki Kim</name><affiliations><json:string>Otitis Media Research Center, Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota</json:string></affiliations></json:item></author><arkIstex>ark:/67375/HXZ-XV76BB0D-F</arkIstex><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Mucoid otitis media (MOM) is characterized by viscous fluid, high in mucin concentration, which accumulates in the middle ear cavity. Recent studies suggest that initial infection in the middle ear cleft may be key to the development of MOM. However, factors of the initial infection attributed to the stimulation of mucin production are not clearly understood. This study demonstrated that tumor necrosis factor (TNF)—α, a proinflammatory cytokine in mucoid effusion, markedly increased Muc2 mucin mRNA expression in middle ear epithelium, in a time- and dose-dependent manner. Parallel to this was a marked increase in mucin glycoprotein in middle ear fluid. Also, TNF-α demonstrated an autocrine and/or paracrine effect on the expression of endogenous TNF-α gene in the middle ear, which may contribute to the production of mucin in this study. These findings suggest that TNF-α plays an important role in the development of MOM by stimulating mucin metabolism.</abstract><qualityIndicators><score>6.085</score><pdfWordCount>4309</pdfWordCount><pdfCharCount>25075</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>6</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><pdfWordsPerPage>718</pdfWordsPerPage><pdfText>true</pdfText><refBibsNative>true</refBibsNative><abstractWordCount>148</abstractWordCount><abstractCharCount>964</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—α: Potential Cause for Mucoid Otitis Media</title><pmid><json:string>10950784</json:string></pmid><genre><json:string>research-article</json:string></genre><host><title>The Journal of Infectious Diseases</title><language><json:string>unknown</json:string></language><issn><json:string>0022-1899</json:string></issn><eissn><json:string>1537-6613</json:string></eissn><publisherId><json:string>jid</json:string></publisherId><volume>182</volume><issue>3</issue><pages><first>882</first><last>887</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>2000</json:string></date><geogName></geogName><orgName><json:string>Clontech, Palo Alto</json:string><json:string>University of Minnesota School of Medicine</json:string><json:string>Lions Research Bldg</json:string><json:string>National Institutes of Health</json:string><json:string>Veterans Affairs Medical Center, Minneapolis</json:string><json:string>Multiple District Hearing Foundation, and National Organization for Hearing Research</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>C. Bullae</json:string><json:string>Jizhen Lin</json:string><json:string>George L. Adams</json:string><json:string>Steven K. Juhn</json:string><json:string>Carol Basbaum</json:string></persName><placeName><json:string>America</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>[23]</json:string><json:string>[6]</json:string><json:string>Smith et al. [15]</json:string><json:string>[33]</json:string><json:string>[8]</json:string><json:string>[19, 20]</json:string><json:string>[28, 29]</json:string><json:string>[1]</json:string><json:string>[32]</json:string><json:string>[26, 27]</json:string><json:string>[31]</json:string><json:string>[2, 3]</json:string><json:string>[5]</json:string><json:string>[15]</json:string><json:string>[30]</json:string><json:string>Lin et al.</json:string><json:string>Riedy et al. [14]</json:string><json:string>[7]</json:string><json:string>[25]</json:string><json:string>[9]</json:string><json:string>Goldie et al. [4]</json:string><json:string>[24]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/HXZ-XV76BB0D-F</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - microbiology</json:string><json:string>2 - infectious diseases</json:string><json:string>2 - immunology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - microbiology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Infectious Diseases</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Immunology and Allergy</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>2000</publicationDate><copyrightDate>2000</copyrightDate><doi><json:string>10.1086/315767</json:string></doi><id>8834A29A576FC54DF337614048EF5CA0F08063F5</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-XV76BB0D-F/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-XV76BB0D-F/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/HXZ-XV76BB0D-F/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—<hi rend="italic">α</hi>: Potential Cause for Mucoid Otitis Media</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>The University of Chicago Press</publisher><availability><licence>© 2000 by the Infectious Diseases Society of America</licence></availability><date type="Copyright" when="2000">2000</date><date type="published">2000</date></publicationStmt><notesStmt><note type="content-type" source="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="publication-type" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—<hi rend="italic">α</hi>: Potential Cause for Mucoid Otitis Media</title><author xml:id="author-0000" role="corresp"><persName><surname>Lin</surname><forename type="first">Jizhen</forename></persName><affiliation><orgName type="institution">Otitis Media Research Center, Department of Otolaryngology</orgName><address><addrLine>Minneapolis, Minnesota</addrLine></address></affiliation></author><author xml:id="author-0001"><persName><surname>Haruta</surname><forename type="first">Atsushi</forename></persName><affiliation><orgName type="institution">Otitis Media Research Center, Department of Otolaryngology</orgName><address><addrLine>Minneapolis, Minnesota</addrLine></address></affiliation></author><author xml:id="author-0002"><persName><surname>Kawano</surname><forename type="first">Hirokazu</forename></persName><affiliation><orgName type="institution">Otitis Media Research Center, Department of Otolaryngology</orgName><address><addrLine>Minneapolis, Minnesota</addrLine></address></affiliation></author><author xml:id="author-0003"><persName><surname>Ho</surname><forename type="first">Samuel B.</forename></persName><affiliation><orgName type="institution">Otitis Media Research Center, Department of Medicine</orgName><address><addrLine>Minneapolis, Minnesota</addrLine></address></affiliation><affiliation><orgName type="institution">Otitis Media Research Center, Department of Veterans Affairs Medical Center</orgName><address><addrLine>Minneapolis, Minnesota</addrLine></address></affiliation></author><author xml:id="author-0004"><persName><surname>Adams</surname><forename type="first">George L.</forename></persName><affiliation><orgName type="institution">Otitis Media Research Center, Department of Otolaryngology</orgName><address><addrLine>Minneapolis, Minnesota</addrLine></address></affiliation></author><author xml:id="author-0005"><persName><surname>Juhn</surname><forename type="first">Steven K.</forename></persName><affiliation><orgName type="institution">Otitis Media Research Center, Department of Otolaryngology</orgName><address><addrLine>Minneapolis, Minnesota</addrLine></address></affiliation></author><author xml:id="author-0006"><persName><surname>Kim</surname><forename type="first">Youngki</forename></persName><affiliation><orgName type="institution">Otitis Media Research Center, Department of Pediatrics, University of Minnesota School of Medicine</orgName><address><addrLine>Minneapolis, Minnesota</addrLine></address></affiliation></author><idno type="istex">8834A29A576FC54DF337614048EF5CA0F08063F5</idno><idno type="ark">ark:/67375/HXZ-XV76BB0D-F</idno><idno type="DOI">10.1086/315767</idno></analytic><monogr><title level="j" type="main">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="hwp">jinfdis</idno><idno type="publisher-id">jid</idno><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published">2000</date><biblScope unit="vol">182</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="882">882</biblScope><biblScope unit="page" to="887">887</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><encodingDesc><schemaRef type="ODD" url="https://xml-schema.delivery.istex.fr/tei-istex.odd"></schemaRef><appInfo><application ident="pub2tei" version="1.0.41" when="2020-04-06"><label>pub2TEI-ISTEX</label><desc>A set of style sheets for converting XML documents encoded in various scientific publisher formats into a common TEI format.
<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract><p>Mucoid otitis media (MOM) is characterized by viscous fluid, high in mucin concentration, which accumulates in the middle ear cavity. Recent studies suggest that initial infection in the middle ear cleft may be key to the development of MOM. However, factors of the initial infection attributed to the stimulation of mucin production are not clearly understood. This study demonstrated that tumor necrosis factor (TNF)—<hi rend="italic">α</hi>, a proinflammatory cytokine in mucoid effusion, markedly increased Muc2 mucin mRNA expression in middle ear epithelium, in a time- and dose-dependent manner. Parallel to this was a marked increase in mucin glycoprotein in middle ear fluid. Also, TNF-<hi rend="italic">α</hi> demonstrated an autocrine and/or paracrine effect on the expression of endogenous TNF-<hi rend="italic">α</hi> gene in the middle ear, which may contribute to the production of mucin in this study. These findings suggest that TNF-<hi rend="italic">α</hi> plays an important role in the development of MOM by stimulating mucin metabolism.</p></abstract><textClass ana="subject"><keywords scheme="heading"><term>Major Articles</term></keywords></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc><revisionDesc><change when="2020-04-06" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-XV76BB0D-F/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-title>The Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>The Journal of Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/315767</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Major Articles</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—<italic>α</italic>: Potential Cause for Mucoid Otitis Media</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name><surname>Lin</surname><given-names>Jizhen</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref rid="cor1" ref-type="corresp"></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Haruta</surname><given-names>Atsushi</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Kawano</surname><given-names>Hirokazu</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Ho</surname><given-names>Samuel B.</given-names></name><xref ref-type="aff" rid="AFF2"><sup>2</sup></xref><xref ref-type="aff" rid="AFF4"><sup>4</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Adams</surname><given-names>George L.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Juhn</surname><given-names>Steven K.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Kim</surname><given-names>Youngki</given-names></name><xref ref-type="aff" rid="AFF3"><sup>3</sup></xref>
</contrib>
<aff id="AFF1"><sup>1</sup><institution>Otitis Media Research Center, Department of Otolaryngology</institution>, <addr-line>Minneapolis, Minnesota</addr-line></aff>
<aff id="AFF2"><sup>2</sup><institution>Otitis Media Research Center, Department of Medicine</institution>, <addr-line>Minneapolis, Minnesota</addr-line></aff>
<aff id="AFF3"><sup>3</sup><institution>Otitis Media Research Center, Department of Pediatrics, University of Minnesota School of Medicine</institution>, <addr-line>Minneapolis, Minnesota</addr-line></aff>
<aff id="AFF4"><sup>4</sup><institution>Otitis Media Research Center, Department of Veterans Affairs Medical Center</institution>, <addr-line>Minneapolis, Minnesota</addr-line></aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Jizhen Lin, Room 216, Lions Research Bldg., 2001 6th St. SE, Minneapolis MN 55455 (<email>linxx004@tc.umn.edu</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<month>9</month>
<year>2000</year>
</pub-date>
<volume>182</volume>
<issue>3</issue>
<fpage>882</fpage>
<lpage>887</lpage>
<history>
<date date-type="received">
<day>13</day>
<month>3</month>
<year>2000</year>
</date>
<date date-type="rev-recd">
<day>15</day>
<month>5</month>
<year>2000</year>
</date>
</history>
<copyright-statement>© 2000 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2000</copyright-year>
<abstract>
<p>Mucoid otitis media (MOM) is characterized by viscous fluid, high in mucin concentration, which accumulates in the middle ear cavity. Recent studies suggest that initial infection in the middle ear cleft may be key to the development of MOM. However, factors of the initial infection attributed to the stimulation of mucin production are not clearly understood. This study demonstrated that tumor necrosis factor (TNF)—<italic>α</italic>, a proinflammatory cytokine in mucoid effusion, markedly increased Muc2 mucin mRNA expression in middle ear epithelium, in a time- and dose-dependent manner. Parallel to this was a marked increase in mucin glycoprotein in middle ear fluid. Also, TNF-<italic>α</italic> demonstrated an autocrine and/or paracrine effect on the expression of endogenous TNF-<italic>α</italic> gene in the middle ear, which may contribute to the production of mucin in this study. These findings suggest that TNF-<italic>α</italic> plays an important role in the development of MOM by stimulating mucin metabolism.</p>
</abstract>
</article-meta>
</front>
<body>
<p>Mucoid otitis media (MOM) is the leading cause of acquired hearing loss in children and thus has a critical impact on development of language, conceptual thinking, and overall social and economic performance. MOM is characterized by the accumulation of viscous fluid in the middle ear cavity. Effusion from humans with MOM contains high measures of mucin concentration when purified without degradation [<xref ref-type="bibr" rid="R1">1</xref>]. Mucin is an important structural component of the mucus that blankets the middle ear and eustachian tube. Under normal conditions, mucin is synthesized and secreted to protect and defend the epithelium of the middle ear, thereby trapping various microorganisms. Overproduction of mucin tremendously increases the viscosity of the mucus blanket and middle ear effusion [<xref ref-type="bibr" rid="R2">2</xref>, <xref ref-type="bibr" rid="R3">3</xref>] because of the gel-forming ability of mucin glycoproteins. This increase in viscosity can lead to dysfunction of the mucociliary transport system of the middle ear and eustachian tube and impede clearance of fluid from the middle ear cavity.</p>
<p>In a study of specific pathogen—free rats, <xref ref-type="bibr" rid="R4">Goldie et al. [4]</xref> found that obstruction of the eustachian tube did not lead to the development of mucoid effusion in the middle ear cavity, unless there was concomitant or prior challenge to the middle ear cleft. This challenge was thought to be related to bacterial infection in the middle ear and stimulation of the mucin metabolism of the mucosa. However, the factors that modulate production and metabolism of mucin in middle ear epithelial cells after the bacterial infection of the middle ear are poorly understood.</p>
<p>A history of ear infection is commonly noted in the clinical records of patients with MOM [<xref ref-type="bibr" rid="R5">5</xref>]. Although bacteria are not often detected in human mucoid effusion [<xref ref-type="bibr" rid="R6">6</xref>], an important proinflammatory cytokine, tumor necrosis factor (TNF)—<italic>α</italic>, is present in MOM. TNF-<italic>α</italic> has recently been shown to stimulate secretion of mucous glycoprotein in cultured epithelial cells from the middle ear [<xref ref-type="bibr" rid="R7">7</xref>], which suggests that TNF-<italic>α</italic> is involved in the regulation of mucin genes in the middle ear. Therefore, we hypothesized that TNF-<italic>α</italic> plays a role in the pathogenesis of MOM by stimulating the mucin synthesis of middle ear epithelial cells. We have recently shown that the Muc2 mucin gene is expressed in epithelial cells in the middle ear of rats [<xref ref-type="bibr" rid="R8">8</xref>]. In this study, we investigated whether TNF-<italic>α</italic>, inoculated into the middle ear cavity of specific pathogen—free rats, up-regulated Muc2 mucin gene expression in the middle ear cleft and mucin in the middle ear fluid in vivo.</p>
<sec sec-type="materials|methods">
<title>Materials and Methods</title>
<sec>
<title>Experimental design</title>
<p>Specific pathogen—free Sprague-Dawley rats of similar age and weight (∼250 g each) were used for this study. To examine the effect of TNF-<italic>α</italic> on mucin production over time, both middle ears of 21 rats were inoculated with 5-ng/<italic>µ</italic>L TNF-<italic>α</italic> in 50 <italic>µ</italic>L of PBS, and 21 control rats received PBS alone. Animals were sacrificed in groups of 7 at 1, 6, or 18 h after inoculation. Mucin or mucin-like glycoproteins were purified by cesium chloride density-gradient centrifugation and were quantified by protein assays. Mucin mRNA in the middle ear mucosa was identified by use of known rodent mucin cDNA probes and semiquantitated by Northern analysis.</p>
<p>To assess whether TNF-<italic>α</italic> had a dose-dependent effect on mucin mRNA, 3 additional groups of 7 rats each were inoculated with TNF-<italic>α</italic> at concentrations of 0, 2.5, or 5 ng/<italic>µ</italic>L and were killed 18 h later. Total RNA was isolated for each group for evaluation of mucin gene expression by use of mucin cDNA probes.</p>
<p>To evaluate whether an increase in mucin mRNA was due to increased transcription of mucin mRNA, expression of mucin mRNA was compared among 4 additional groups of 7 rats each, each group being treated as follows: PBS; PBS and TNF-<italic>α</italic> (5 ng/mL); actinomycin D (6 <italic>µ</italic>g/mL) inoculated 30 min before PBS; or actinomycin D (6 <italic>µ</italic>g/mL) inoculated 30 min before PBS and TNF-<italic>α</italic> (5 ng/mL). Animals were killed 18 h after treatment.</p>
<p>To evaluate whether endogenous TNF-<italic>α</italic> was involved, expression of the TNF-<italic>α</italic> gene in the above groups of rats treated for 18 h with TNF-<italic>α</italic> (5 ng/mL) or PBS was quantified by reverse transcription—polymerase chain reaction (RT-PCR) and competitive RT-PCR.</p>
</sec>
<sec>
<title>Inoculation of TNF-α into the middle ear cavity of rats</title>
<p>Rats were anesthetized with ketamine HC1 (40 mg/kg) and xylazine (8 mg/kg). A ventral incision was made under sterile conditions, and the ventral surface of the bullae was exposed. A tiny hole was made with a 27-gauge needle to vent the bullae, and another hole was made for the inoculation. After both middle ear cavities were inoculated, the holes were sealed with sterile bone wax, and the incision was closed.</p>
</sec>
<sec>
<title>Harvest of the bullae and middle ear fluid</title>
<p>At each of the time points listed above, rats were anesthetized with ketamine HCl (80 mg/kg) and xylazine (16 mg/kg) and were killed by decapitation, and both bullae were immediately removed. Effusions were collected through an opening in the bottom of the bullae before the middle ear cavity was washed with PBS containing 40 U/mL RNase inhibitor, 1 m<italic>M</italic> phenylmethylsulfonyl fluoride, and 15 m<italic>M</italic> CHAPS. Effusions from each group were pooled and stored at −70°C. Bullae were injected with 4 M guanidine isothiocyanate for isolation of total RNA by lavage [<xref ref-type="bibr" rid="R8">8</xref>].</p>
</sec>
<sec>
<title>Quantitation of mucin</title>
<p>Mucin or mucin-like glycoproteins were purified by a method described elsewhere [<xref ref-type="bibr" rid="R9">9</xref>]. Briefly, middle ear effusion proteins were dissociated from each other in reductant (100 mM dithiothreitol) and denaturant (4 M guanidine hydrochloride) solutions for 24 h, carboxylated in 250 m<italic>M</italic> iodoamylamide for 24 h, density-separated in a cesium chloride solution (1.4 g/mL) by ultracentrifugation at 160,000 <italic>g</italic> for 72 h, and fractionated at 1 mL. For each fraction, buoyant cesium chloride density was measured by weight, carbohydrate concentration was determined by hexose assay, and protein concentration was ascertained by bicinchoninic acid protein assay [<xref ref-type="bibr" rid="R9">9</xref>]. The ratio of carbohydrate to protein was calculated as hexose concentration over protein concentration. Fractions with a cesium chloride density of ∼1.4 g/mL that also had a high concentration of hexose and low concentration of protein (hexose-to-protein ratio of ∼2:1) were defined as mucin or mucin-like glycoproteins [<xref ref-type="bibr" rid="R9">9</xref>].</p>
</sec>
<sec>
<title>Northern analysis of steady-state mucin mRNA</title>
<p>Northern analysis of steady-state mucin mRNAs was done as described elsewhere [<xref ref-type="bibr" rid="R8">8</xref>]. Briefly, ∼20 <italic>µ</italic>g of total RNA was denatured and size-separated by electrophoresis, transferred onto a nylon membrane, crosslinked to the membrane under UV light, and hybridized at 65°C for 2 h with rapid-hybridization buffer containing a <sup>32</sup>P-radiolabeled mucin Muc2 cDNA probe with a radioactivity of 2 × 10<sup>6</sup> cpm/mL. The blot was first washed under stringent conditions and then exposed on a Kodak XAR film at −80°C. The blot was stripped with 0.1% SDS and reprobed, respectively, with Muc1 (GenBank accession no. AF007554), Muc3 [<xref ref-type="bibr" rid="R10">10</xref>], Muc4 [<xref ref-type="bibr" rid="R11">11</xref>], Muc5ac [<xref ref-type="bibr" rid="R12">12</xref>], and <italic>β</italic>-actin (housekeeping gene) cDNA probes. The actual amount of RNA loaded onto each lane was adjusted by densitometry, whereby hybridizing signals were digitalized (Molecular Analyst; Bio-Rad, Hercules, CA) to allow for direct comparison of the intensity of each signal band.</p>
</sec>
<sec>
<title>Quantitation of expression of the TNF-α gene</title>
<p>Expression of the TNF-<italic>α</italic> gene was screened by RT-PCR. The TNF-<italic>α</italic> primer sequences were derived from mRNA for TNF-<italic>α</italic> [<xref ref-type="bibr" rid="R13">13</xref>] and were amplified by gene-specific primer pairs: sense, 5′-CCACCACGCTCTTCTGTCTA-3′; antisense, 5′-GGCGGAGAGGAGGCTGACTT-3′. The housekeeping gene GAPDH was used to control the amplification efficiency of RT-PCR for each sample tested. RT-PCR was done as described elsewhere [<xref ref-type="bibr" rid="R8">8</xref>].</p>
<p>The difference between control and experimental groups was measured by competitive RT-PCR, as described elsewhere [<xref ref-type="bibr" rid="R9">9</xref>]. For construction of a control repetitive standard of the TNF-<italic>α</italic> gene (TNF-<italic>α</italic> CRS), a fragment of the TNF-<italic>α</italic> gene was amplified by use of the following compound primer pair: sense, 5′-<underline>TAATACGACTCACTATAGGGCGA</underline>CCACCACGCTCTTCTGTCTA-3′ (T<sub>7</sub> sequences [underlined] +19 mers of TNF-<italic>α</italic> sequences); antisense, 5′-ACCTGGGAGTAGATAAGGTAGGCGGAGAGGAGGCTGACTT-3′.</p>
<p>Samples of RNA isolated from the middle ear were reversetranscribed into cDNA by use of oligo-dT and murine leukemia virus (MuLV) RT (at 42°C for 25 min). After RT, the above compound primer pair, as well as Taq DNA polymerase, were added to the above reaction mixture to amplify a fragment of cDNA (cDNA for TNF-<italic>α</italic> CRS, 100-bp deletion, compared with the product of the wild-type TNF-<italic>α</italic>). The cDNA for TNF-<italic>α</italic> CRS was isolated by electrophoresis onto a 2% agarose gel, purified by running it through a spin column (GenElute; Supelco, Beliefonte, PA), and transcribed into RNA (RNA for TNF-<italic>α</italic> CRS) in vitro by T<sub>7</sub> RNA polymerase by use of a Megascript kit (Clontech, Palo Alto, CA). The RNA for TNF-<italic>α</italic> CRS was quantitated by spectrophotometry at 260 nm.</p>
<p>Competitive RT-PCR was done by adding decreasing amounts of TNF-<italic>α</italic> CRS from 2.5 <italic>µ</italic>g/mL to 0.026 <italic>µ</italic>g/mL to a constant amount of sample RNA (1 <italic>µ</italic>g/microtube) in 6 successive microtubes. Each mixture was then subjected to the RT-PCR procedure. RT was done by use of oligo-dT and MuLV RT. PCR was done by use of gene-specific primers and Taq polymerase. Products of the RT-PCR were run on 2% agarose gels for ∼20 min to allow for the bands from the sample and from the control (CRS) to be separated. Incorporation of ethidium bromide into 2 bands was corrected, as described by <xref ref-type="bibr" rid="R14">Riedy et al. [14]</xref>. The point at which cDNA from the corrected TNF-<italic>α</italic> CRS equaled cDNA from wildtype TNF-<italic>α</italic> provided a concentration of TNF-<italic>α</italic> mRNA transcript.</p>
</sec>
</sec>
<sec sec-type="results">
<title>Results</title>
<sec>
<title>Gross examination of effusions from the middle ear</title>
<p>All rats that received an inoculation of 5-ng/<italic>µ</italic>L TNF-<italic>α</italic> (250 ng/ear) developed fluid. The average amount of effusion produced by inoculation of TNF-<italic>α</italic> increased from 53 <italic>µ</italic>L/ear at 1 h to 71 <italic>µ</italic>L at 6 h and peaked at 97 <italic>µ</italic>L at 18 h. Control ears (inoculated with PBS) had less effusion, averaging 31 <italic>µ</italic>L/ear at 1 h and declining to 24 <italic>µ</italic>L at 6 h and 5 <italic>µ</italic>L by 18 h.</p>
</sec>
<sec>
<title>Quantitation of secreted mutins</title>
<p>Glycoproteins with a buoyant density of ∼1.4 g/mL, overlapping with a ratio of carbohydrate to protein of ∼2:1 after density centrifugation with cesium chloride, were defined as mucin or mucin-like glycoproteins [<xref ref-type="bibr" rid="R9">9</xref>]. The results are presented in <xref ref-type="fig" rid="F1">figure 1</xref>. Levels of mucin or mucin-like glycoproteins increased in animals treated with TNF-<italic>α</italic> in a time-dependent manner (18h > 6h > 1h; <xref ref-type="fig" rid="F1">figure 1<italic>B</italic></xref>), whereas levels in animals treated with PBS alone did not increase (<xref ref-type="fig" rid="F1">figure 1<italic>A</italic></xref>). The magnitude of increase in mucin or mucin-like glycoproteins was 1-fold at 1 h, 1.5-fold at 6 h, and 2.1-fold at 18 h in animals treated with TNF-<italic>α</italic>, compared with that in control (PBS) animals.</p>
</sec>
<sec>
<title>Expression of mucin genes</title>
<p>Hybridization of the blot with mucin cDNA probes from Muc1 to Muc5ac demonstrated that tracheal tissue (positive control) expressed Muc2 and Muc5ac but not Muc1, Muc3, or Muc4; intestinal tissue (another positive control) expressed Muc2 and Muc3 but not Muc1, Muc4, or Muc5ac; fibroblasts (negative control) did not express mucin genes; and middle ear tissue expressed Muc2 but not Muc1, Muc3, Muc4, or Muc5ac by Northern analysis. The RNA from control animals showed a faint 13-kb band that hybridized with Muc2 at all time points studied. TNF-<italic>α</italic> enhanced expression of the Muc2 mucin gene in middle ear epithelial cells in a timedependent manner (<xref ref-type="fig" rid="F2">figure 2</xref>). Digitalized analysis of levels of Muc2 mRNA for all time points studied (data normalized to expression of the gene for <italic>β</italic>-actin) indicated that the magnitude of increase in Muc2 mucin gene expression was ∼1.9-fold at 1 h, 3.8-fold at 6 h, and 5.7-fold at 18 h in animals treated with TNF-<italic>α</italic>, compared with that in control animals. TNF-<italic>α</italic> was found to stimulate expression of Muc2 mucin mRNA in a dosedependent manner (<xref ref-type="fig" rid="F3">figure 3<italic>A</italic></xref>). After transcription of mRNA was blocked by actinomycin D (6 <italic>µ</italic>g/mL), TNF-<italic>α</italic> (5 ng/<italic>µ</italic>L) did not increase levels of Muc2 mRNA (<xref ref-type="fig" rid="F3">figure 3<italic>B</italic></xref>), which suggests a control point of mRNA at the transcription level.</p>
</sec>
<sec>
<title>Self-induction of the TNF-α gene</title>
<p>Expression of the endogenous TNF-<italic>α</italic> gene at 18 h in TNF-<italic>α</italic>—treated rats appeared to be increased, compared with that in control rats, after data was normalized to expression of the gene for GAPDH. Quantitation of this increase by competitive RT-PCR confirmed that the level of the TNF-<italic>α</italic> gene at 18 h in rats with recombinant human TNF-<italic>α</italic> inoculation was 0.16 <italic>µ</italic>g/mL, ∼2.5 times that of controls (<xref ref-type="fig" rid="F4">figure 4</xref>). No TNF-<italic>α</italic> gene product was found in the controls by RT-PCR (omission of MuLV RT, Taq polymerase, primers, and samples), which indicates no contamination of samples.</p>
</sec>
</sec>
<sec sec-type="discussion">
<title>Discussion</title>
<p>TNF-<italic>α</italic> is a 17-kDa polypeptide that binds to specific receptors for TNF (TR55 and TR75) [<xref ref-type="bibr" rid="R15">15</xref>] on the cellular membrane. This binding creates biologic signals along various pathways linked to effector molecules and thus elicits diverse biologic responses, such as killing of tumors [<xref ref-type="bibr" rid="R16">16</xref>], host-defense reactions [<xref ref-type="bibr" rid="R17">17</xref>, <xref ref-type="bibr" rid="R18">18</xref>], and immune and inflammatory reactions [<xref ref-type="bibr" rid="R19">19</xref>, <xref ref-type="bibr" rid="R20">20</xref>]. TNF-<italic>α</italic> plays an important role in defense against bacterial infection [<xref ref-type="bibr" rid="R21">21</xref>] and viruses [<xref ref-type="bibr" rid="R22">22</xref>]. Animals with knockout of the TNF-<italic>α</italic> gene have been shown to be unable to survive infection [<xref ref-type="bibr" rid="R17">17</xref>, <xref ref-type="bibr" rid="R18">18</xref>]. Conversely, overexpression of the gene for TNF-<italic>α</italic> often causes life-threatening states, such as shock and wasting.</p>
<p>TNF-<italic>α</italic> plays an important role in a variety of inflammatory reactions, and it has been recognized as a major mediator in the development of septic shock after gram-negative bacterial infection [<xref ref-type="bibr" rid="R19">19</xref>, <xref ref-type="bibr" rid="R20">20</xref>]. The mechanism by which TNF-<italic>α</italic> acts involves up-regulation or activation of targeted genes, such as interleukin-1 [<xref ref-type="bibr" rid="R23">23</xref>], phospholipase [<xref ref-type="bibr" rid="R24">24</xref>], or TNF-<italic>α</italic> itself [<xref ref-type="bibr" rid="R25">25</xref>]. These genes are actively involved in inflammatory responses. Sources of TNF-<italic>α</italic> include macrophages, monocytes [<xref ref-type="bibr" rid="R26">26</xref>, <xref ref-type="bibr" rid="R27">27</xref>], and epithelial cells in the middle ear (unpublished data). Its release is postulated to occur subsequently to the binding of the lipid A portion of lipopolysaccharide to a specific receptor for lipopolysaccharide (CD14) or through the integration of lipid A into the cellular membrane [<xref ref-type="bibr" rid="R28">28</xref>, <xref ref-type="bibr" rid="R29">29</xref>]. The presence of lipopolysaccharide in middle ear fluid [<xref ref-type="bibr" rid="R30">30</xref>] is believed to be linked to the induction of TNF-<italic>γ</italic>.</p>
<p>TNF-<italic>α</italic> markedly increased the steady-state level of Muc2 mucin mRNA in middle ear epithelial cells of rats in this study in a dose- and time-dependent manner, beginning at 1 h and continuing to 18 h. This pattern did not occur in control animals, which indicates that TNF-<italic>α</italic> induces Muc2 mucin in the middle ear. The increase in steady-state Muc2 mRNA appeared to be related to increased transcription of mRNA, because blocking its transcription with actinomycin D abrogated this up-regulation. The molecular mechanism for this action may involve binding of TNF-<italic>α</italic> to receptors for TNF (dimerization or trimerization of the receptors), transduction of the signal, and activation of transcriptional factors. <xref ref-type="bibr" rid="R15">Smith et al. [15]</xref> demonstrated that the receptor involved in this action appears to be a type I receptor (TR55, a 55-kDa molecule), a member of the TNF-<italic>α</italic> superfamily. Type I TNF-<italic>α</italic> receptors have been shown to inhibit TNF-<italic>α</italic>—mediated action on mucins in the airway in vitro [<xref ref-type="bibr" rid="R31">31</xref>].</p>
<p>After activation of TNF receptors, signal transduction occurs in the protein kinase C pathway. A study of middle ear epithelial cells in primary culture demonstrated reduced secretion of mucin by protein kinase C inhibitor H-7 [<xref ref-type="bibr" rid="R7">7</xref>]. In a study of cultured tracheal epithelial cells, expression of mucin Muc2 mRNA was inhibited by blocking the protein kinase C pathway with calphostin C [<xref ref-type="bibr" rid="R31">31</xref>]. It has recently been demonstrated that factor Sp1 participates in regulation of the Muc2 mucin gene in the airway [<xref ref-type="bibr" rid="R32">32</xref>].</p>
<p>Parallel to the up-regulation of Muc2 mucin mRNA demonstrated in this study was a marked increase in mucin glycoprotein in the middle ear fluid. Although the identity of the middle ear mucin glycoprotein was unclear, it appeared to be Muc2 mucin glycoprotein, because mucin mRNA in the middle ear mucosa hybridized with Muc2 mucin probes but not with Muc1, Muc3, Muc4 (ascites sialoglycoprotein), or Muc5ac mucin cDNA probes, the major mucins in the respiratory and digestive tracts. It is possible that the mucin glycoprotein induced by TNF-<italic>α</italic> in the middle ear fluid is a homologue of human MUC5B mucin, shown to be expressed in human middle ear mucosa [<xref ref-type="bibr" rid="R33">33</xref>]. If so, the sequence of rat Muc5b (a counterpart to human MUC5B) must be different than that of human MUC5B, because Northern analysis of the rat middle ear mRNA in this study showed no hybridizing signals with the human MUC5B cDNA probe (data not shown). Although mucin antibodies might have been helpful in identifying the mucinproducing cells in the middle ear mucosa, it would not have differentiated one mucin type from another because of potential cross-reactions between mucin antibodies [<xref ref-type="bibr" rid="R33">33</xref>]. Therefore, it is unknown at the present time whether a novel mucin is involved in the middle ear.</p>
<p>Interestingly, TNF-<italic>α</italic> demonstrated an autocrine and/or paracrine effect on TNF-<italic>α</italic> gene expression in the middle ear, which may contribute to mucin hyperproductivity in the middle ear cleft, especially in diseased epithelium. The parallel increases in the concentration of mucin glycoprotein in middle ear fluid with that of Muc2 mRNA in epithelial cells between 1 and 18 h after inoculation of TNF-<italic>α</italic> suggests translation of Muc2 mRNA into proteins. TNF-<italic>α</italic> appears to affect more than the transcription level of the Muc2 gene. An in vitro study showed TNF-<italic>α</italic> to be a secretagogue for mucin glycoprotein in middle ear epithelial cells [<xref ref-type="bibr" rid="R7">7</xref>]. TNF-<italic>α</italic>—increased secretion of mucin glycoprotein in vitro may also occur in vivo, although the mechanism for this is not yet understood. The action of TNF-<italic>α</italic> on mucin secretion appeared to be dependent on TNF receptors and protein kinase C [<xref ref-type="bibr" rid="R7">7</xref>].</p>
<p>The TNF-<italic>α</italic>—stimulated secretion of mucous glycoprotein demonstrated in vitro in our previous study [<xref ref-type="bibr" rid="R7">7</xref>], as well as the mucin secretion and up-regulation in Muc2 mucin gene expression shown in vivo in this study, indicate that TNF-<italic>α</italic> is both an inducer of the Muc2 gene and a secretagogue for mucin in the middle ear. These data add support to the hypothesis that TNF-<italic>α</italic> plays an essential role in the development of MOM by stimulating mucin metabolism.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We thank Carol Basbaum for the kind gift of the probe for Muc2 mucin in rats, Barb Bensen for assistance in mucin quantitation, and JoAnn Knox for editorial assistance.</p>
</ack>
<ref-list>
<title>References</title>
<ref id="R1">
<label>1.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Brown</surname><given-names>DT</given-names></name>
<name><surname>Litt</surname><given-names>M</given-names></name>
<name><surname>Potsic</surname><given-names>WP</given-names></name>
</person-group>
<article-title>A study of mucus glycoproteins in secretory otitis media</article-title>
<source>Arch Otolaryngol</source>
<year>1985</year>
<volume>111</volume>
<fpage>688</fpage>
<lpage>95</lpage>
</nlm-citation>
</ref>
<ref id="R2">
<label>2.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Carrie</surname><given-names>S</given-names></name>
<name><surname>Hutton</surname><given-names>DA</given-names></name>
<name><surname>Birchall</surname><given-names>JP</given-names></name>
<name><surname>Green</surname><given-names>GG</given-names></name>
<name><surname>Pearson</surname><given-names>JP</given-names></name>
</person-group>
<article-title>Otitis media with effusion: components which contribute to the viscous properties</article-title>
<source>Acta Otolaryngol</source>
<year>1992</year>
<volume>112</volume>
<fpage>504</fpage>
<lpage>11</lpage>
</nlm-citation>
</ref>
<ref id="R3">
<label>3.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>FitzGerald</surname><given-names>JE</given-names></name>
<name><surname>Green</surname><given-names>GG</given-names></name>
<name><surname>Birchall</surname><given-names>JP</given-names></name>
<name><surname>Pearson</surname><given-names>JP</given-names></name>
</person-group>
<article-title>Mucolytic agents and otitis media with effusion</article-title>
<source>Biomed Pharmacother</source>
<year>1988</year>
<volume>42</volume>
<fpage>505</fpage>
<lpage>11</lpage>
</nlm-citation>
</ref>
<ref id="R4">
<label>4.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Goldie</surname><given-names>P</given-names></name>
<name><surname>Hellstrom</surname><given-names>S</given-names></name>
<name><surname>Johansson</surname><given-names>U</given-names></name>
</person-group>
<article-title>Vascular events in experimental otitis media models: a comparative study</article-title>
<source>ORL J Otorhinolaryngol Relat Spec</source>
<year>1990</year>
<volume>52</volume>
<fpage>104</fpage>
<lpage>12</lpage>
</nlm-citation>
</ref>
<ref id="R5">
<label>5.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Giebink</surname><given-names>GS</given-names></name>
<name><surname>Mills</surname><given-names>EL</given-names></name>
<name><surname>Huff</surname><given-names>JS</given-names></name>
<etal></etal>
</person-group>
<article-title>The microbiology of serous and mucoid otitis media</article-title>
<source>Pediatrics</source>
<year>1979</year>
<volume>63</volume>
<fpage>915</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="R6">
<label>6.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Himi</surname><given-names>T</given-names></name>
<name><surname>Suzuki</surname><given-names>T</given-names></name>
<name><surname>Kodama</surname><given-names>H</given-names></name>
<name><surname>Takezawa</surname><given-names>H</given-names></name>
<name><surname>Kataura</surname><given-names>A</given-names></name>
</person-group>
<article-title>Immunologic characteristics of cytokines in otitis media with effusion</article-title>
<source>Ann Otol Rhinol Laryngol Suppl</source>
<year>1992</year>
<volume>157</volume>
<fpage>21</fpage>
<lpage>5</lpage>
</nlm-citation>
</ref>
<ref id="R7">
<label>7.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Lin</surname><given-names>J</given-names></name>
<name><surname>Kim</surname><given-names>Y</given-names></name>
<name><surname>Juhn</surname><given-names>SK</given-names></name>
</person-group>
<article-title>Increase of mucous glycoprotein secretion by tumor necrosis factor—<italic>α</italic> via a protein kinase C—dependent mechanism in cultured chinchilla middle ear epithelial cells</article-title>
<source>Ann Otol Rhinol Laryngol</source>
<year>1998</year>
<volume>107</volume>
<fpage>213</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="R8">
<label>8.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Lin</surname><given-names>J</given-names></name>
<name><surname>Ho</surname><given-names>S</given-names></name>
<name><surname>Schekels</surname><given-names>L</given-names></name>
<name><surname>Paparella</surname><given-names>MM</given-names></name>
<name><surname>Kim</surname><given-names>Y</given-names></name>
</person-group>
<article-title>Mucin gene expression in the rat middle ear: an improved method for RNA harvest</article-title>
<source>Ann Otol Rhinol Laryngol</source>
<year>1999</year>
<volume>108</volume>
<fpage>762</fpage>
<lpage>8</lpage>
</nlm-citation>
</ref>
<ref id="R9">
<label>9.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Lin</surname><given-names>J</given-names></name>
<name><surname>Vambutas</surname><given-names>A</given-names></name>
<name><surname>Haruta</surname><given-names>A</given-names></name>
<name><surname>Paparella</surname><given-names>MM</given-names></name>
<name><surname>Giebink</surname><given-names>GS</given-names></name>
<name><surname>Kim</surname><given-names>Y</given-names></name>
</person-group>
<article-title>Pneumococcus activation of the 5-lipoxygenase pathway and production of glycoproteins in the middle ear of rats</article-title>
<source>J Infect Dis</source>
<year>1999</year>
<volume>179</volume>
<fpage>1145</fpage>
<lpage>51</lpage>
</nlm-citation>
</ref>
<ref id="R10">
<label>10.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Shekels</surname><given-names>LL</given-names></name>
<name><surname>Hunninghake</surname><given-names>DA</given-names></name>
<name><surname>Tisdale</surname><given-names>AS</given-names></name>
<etal></etal>
</person-group>
<article-title>Cloning and characterization of mouse intestinal MUC3 mucin: 3′ sequence contains epidermalgrowth factor—like domains</article-title>
<source>Biochem J</source>
<year>1998</year>
<volume>330</volume>
<fpage>1301</fpage>
<lpage>8</lpage>
</nlm-citation>
</ref>
<ref id="R11">
<label>11.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Wu</surname><given-names>K</given-names></name>
<name><surname>Fregien</surname><given-names>N</given-names></name>
<name><surname>Carraway</surname><given-names>KL</given-names></name>
</person-group>
<article-title>Molecular cloning and sequencing of the mucin subunit of a heterodimeric, bifunctional cell surface glycoprotein complex of ascites rat mammary adenocarcinoma cells</article-title>
<source>J Biol Chem</source>
<year>1994</year>
<volume>269</volume>
<fpage>11950</fpage>
<lpage>5</lpage>
</nlm-citation>
</ref>
<ref id="R12">
<label>12.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Shekels</surname><given-names>LL</given-names></name>
<name><surname>Lyftogt</surname><given-names>C</given-names></name>
<name><surname>Kieliszewski</surname><given-names>M</given-names></name>
<name><surname>Filie</surname><given-names>JD</given-names></name>
<name><surname>Kozak</surname><given-names>CA</given-names></name>
<name><surname>Ho</surname><given-names>SB</given-names></name>
</person-group>
<article-title>Mouse gastric mucin: cloning and chromosomal location</article-title>
<source>Biochem J</source>
<year>1995</year>
<volume>311</volume>
<fpage>775</fpage>
<lpage>85</lpage>
</nlm-citation>
</ref>
<ref id="R13">
<label>13.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Estler</surname><given-names>HC</given-names></name>
<name><surname>Grewe</surname><given-names>M</given-names></name>
<name><surname>Gaussling</surname><given-names>R</given-names></name>
<name><surname>Pavlovic</surname><given-names>M</given-names></name>
<name><surname>Decker</surname><given-names>K</given-names></name>
</person-group>
<article-title>Rat tumor necrosis factor—<italic>α</italic>: transcription in rat Kupffer cells and in vitro posttranscriptional processing based on a PCR-derived cDNA</article-title>
<source>Biol Chem Hoppe Seyler</source>
<year>1992</year>
<volume>373</volume>
<fpage>271</fpage>
<lpage>81</lpage>
</nlm-citation>
</ref>
<ref id="R14">
<label>14.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Riedy</surname><given-names>MC</given-names></name>
<name><surname>Timm</surname><given-names>EA</given-names></name>
<name><surname>Stewart</surname><given-names>CC</given-names></name>
</person-group>
<article-title>Quantitative RT-PCR for measuring gene expression</article-title>
<source>Biotechniques</source>
<year>1995</year>
<volume>18</volume>
<fpage>70</fpage>
<lpage>4</lpage>
</nlm-citation>
</ref>
<ref id="R15">
<label>15.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Smith</surname><given-names>CA</given-names></name>
<name><surname>Farrah</surname><given-names>T</given-names></name>
<name><surname>Goodwin</surname><given-names>RG</given-names></name>
</person-group>
<article-title>The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death</article-title>
<source>Cell</source>
<year>1994</year>
<volume>76</volume>
<fpage>959</fpage>
<lpage>62</lpage>
</nlm-citation>
</ref>
<ref id="R16">
<label>16.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Carswell</surname><given-names>EA</given-names></name>
<name><surname>Old</surname><given-names>LJ</given-names></name>
<name><surname>Kassel</surname><given-names>RL</given-names></name>
<name><surname>Green</surname><given-names>S</given-names></name>
<name><surname>Fiore</surname><given-names>N</given-names></name>
<name><surname>Williamson</surname><given-names>B</given-names></name>
</person-group>
<article-title>An endotoxin-induced serum factor that causes necrosis of tumors</article-title>
<source>Proc Natl Acad Sci USA</source>
<year>1975</year>
<volume>72</volume>
<fpage>3666</fpage>
<lpage>70</lpage>
</nlm-citation>
</ref>
<ref id="R17">
<label>17.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Nakane</surname><given-names>A</given-names></name>
<name><surname>Minagawa</surname><given-names>T</given-names></name>
<name><surname>Kato</surname><given-names>K</given-names></name>
</person-group>
<article-title>Endogenous tumor necrosis factor (cachectin) is essential to host resistance against <italic>Listeria monocytogenes</italic> infection</article-title>
<source>Infect Immun</source>
<year>1988</year>
<volume>56</volume>
<fpage>2563</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="R18">
<label>18.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Vaudaux</surname><given-names>P</given-names></name>
<name><surname>Grau</surname><given-names>GE</given-names></name>
<name><surname>Huggler</surname><given-names>E</given-names></name>
<etal></etal>
</person-group>
<article-title>Contribution of tumor necrosis factor to host defense against staphylococci in a guinea pig model of foreign body infections</article-title>
<source>J Infect Dis</source>
<year>1992</year>
<volume>166</volume>
<fpage>58</fpage>
<lpage>64</lpage>
</nlm-citation>
</ref>
<ref id="R19">
<label>19.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Tracey</surname><given-names>KJ</given-names></name>
<name><surname>Fong</surname><given-names>Y</given-names></name>
<name><surname>Hesse</surname><given-names>DG</given-names></name>
<etal></etal>
</person-group>
<article-title>Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia</article-title>
<source>Nature</source>
<year>1987</year>
<volume>330</volume>
<fpage>662</fpage>
<lpage>4</lpage>
</nlm-citation>
</ref>
<ref id="R20">
<label>20.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Oliff</surname><given-names>A</given-names></name>
<name><surname>Defeo-Jones</surname><given-names>D</given-names></name>
<name><surname>Boyer</surname><given-names>M</given-names></name>
<etal></etal>
</person-group>
<article-title>Tumors secreting human TNF/cachectin induce cachexia in mice</article-title>
<source>Cell</source>
<year>1987</year>
<volume>50</volume>
<fpage>555</fpage>
<lpage>63</lpage>
</nlm-citation>
</ref>
<ref id="R21">
<label>21.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Pfeffer</surname><given-names>K</given-names></name>
<name><surname>Matsuyama</surname><given-names>T</given-names></name>
<name><surname>Kundig</surname><given-names>TM</given-names></name>
<etal></etal>
</person-group>
<article-title>Mice deficient for the 55-kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to <italic>L. monocytogenes</italic> infection</article-title>
<source>Cell</source>
<year>1993</year>
<volume>73</volume>
<fpage>457</fpage>
<lpage>67</lpage>
</nlm-citation>
</ref>
<ref id="R22">
<label>22.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Mestan</surname><given-names>J</given-names></name>
<name><surname>Digel</surname><given-names>W</given-names></name>
<name><surname>Mittnacht</surname><given-names>S</given-names></name>
<etal></etal>
</person-group>
<article-title>Antiviral effects of recombinant tumor necrosis factor in vitro</article-title>
<source>Nature</source>
<year>1986</year>
<volume>323</volume>
<fpage>816</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="R23">
<label>23.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Dinarello</surname><given-names>CA</given-names></name>
<name><surname>Cannon</surname><given-names>JG</given-names></name>
<name><surname>Wolff</surname><given-names>SM</given-names></name>
<etal></etal>
</person-group>
<article-title>Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin-1</article-title>
<source>J Exp Med</source>
<year>1986</year>
<volume>163</volume>
<fpage>1433</fpage>
<lpage>50</lpage>
</nlm-citation>
</ref>
<ref id="R24">
<label>24.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Clark</surname><given-names>MA</given-names></name>
<name><surname>Chen</surname><given-names>MJ</given-names></name>
<name><surname>Crooke</surname><given-names>ST</given-names></name>
<name><surname>Bomalaski</surname><given-names>JS</given-names></name>
</person-group>
<article-title>Tumour necrosis factor (cachectin) induces phospholipase A2 activity and synthesis of a phospholipase A2—activating protein in endothelial cells</article-title>
<source>Biochem J</source>
<year>1988</year>
<volume>250</volume>
<fpage>125</fpage>
<lpage>32</lpage>
</nlm-citation>
</ref>
<ref id="R25">
<label>25.</label>
<nlm-citation citation-type="book">
<person-group person-group-type="author">
<name><surname>Kronke</surname><given-names>M</given-names></name>
<name><surname>Schutze</surname><given-names>S</given-names></name>
<name><surname>Scheurich</surname><given-names>P</given-names></name>
<name><surname>Pfizenmaier</surname><given-names>K</given-names></name>
</person-group>
<person-group person-group-type="editor">
<name><surname>Aggarwal</surname><given-names>BB</given-names></name>
<name><surname>Vilcek</surname><given-names>J</given-names></name>
</person-group>
<article-title>TNF signal transduction and TNF-responsive genes</article-title>
<source>Tumor necrosis factor: structure, function, and mechanism of action. Vol 56</source>
<year>1992</year>
<publisher-loc>New York</publisher-loc>
<publisher-name>Marcel Dekker</publisher-name>
<fpage>189</fpage>
<lpage>216</lpage>
</nlm-citation>
</ref>
<ref id="R26">
<label>26.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Fong</surname><given-names>Y</given-names></name>
<name><surname>Lowry</surname><given-names>S</given-names></name>
</person-group>
<article-title>Tumor necrosis factor in the pathophysiology of infection and sepsis</article-title>
<source>Clin Immunol Immunopathol</source>
<year>1990</year>
<volume>55</volume>
<fpage>157</fpage>
<lpage>70</lpage>
</nlm-citation>
</ref>
<ref id="R27">
<label>27.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Urban</surname><given-names>JL</given-names></name>
<name><surname>Shepard</surname><given-names>HM</given-names></name>
<name><surname>Rothstein</surname><given-names>JL</given-names></name>
<name><surname>Sugarman</surname><given-names>BJ</given-names></name>
<name><surname>Schreiber</surname><given-names>H</given-names></name>
</person-group>
<article-title>Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages</article-title>
<source>Proc Natl Acad Sci USA</source>
<year>1986</year>
<volume>83</volume>
<fpage>5233</fpage>
<lpage>7</lpage>
</nlm-citation>
</ref>
<ref id="R28">
<label>28.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Morrison</surname><given-names>DC</given-names></name>
<name><surname>Rudbach</surname><given-names>JA</given-names></name>
</person-group>
<article-title>Endotoxin—cell membrane interactions leading to transmembrane signaling</article-title>
<source>Contemp Top Mol Immunol</source>
<year>1981</year>
<volume>8</volume>
<fpage>187</fpage>
<lpage>218</lpage>
</nlm-citation>
</ref>
<ref id="R29">
<label>29.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Morrison</surname><given-names>DC</given-names></name>
</person-group>
<article-title>The case for specific lipopolysaccharide receptors expressed on mammalian cells</article-title>
<source>Microb Pathog</source>
<year>1989</year>
<volume>7</volume>
<fpage>389</fpage>
<lpage>98</lpage>
</nlm-citation>
</ref>
<ref id="R30">
<label>30.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Ovesen</surname><given-names>T</given-names></name>
<name><surname>Ledet</surname><given-names>T</given-names></name>
</person-group>
<article-title>Bacteria and endotoxin in middle ear fluid and the course of secretory otitis media</article-title>
<source>Clin Otolaryngol</source>
<year>1992</year>
<volume>17</volume>
<fpage>531</fpage>
<lpage>4</lpage>
</nlm-citation>
</ref>
<ref id="R31">
<label>31.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Levine</surname><given-names>SJ</given-names></name>
<name><surname>Larivee</surname><given-names>P</given-names></name>
<name><surname>Logun</surname><given-names>C</given-names></name>
<name><surname>Angus</surname><given-names>CW</given-names></name>
<name><surname>Ognibene</surname><given-names>FP</given-names></name>
<name><surname>Shelhamer</surname><given-names>JH</given-names></name>
</person-group>
<article-title>Tumor necrosis factor—<italic>α</italic> induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells</article-title>
<source>Am J Respir Cell Mol Biol</source>
<year>1995</year>
<volume>12</volume>
<fpage>196</fpage>
<lpage>204</lpage>
</nlm-citation>
</ref>
<ref id="R32">
<label>32.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Nogami</surname><given-names>H</given-names></name>
<name><surname>Ohmori</surname><given-names>H</given-names></name>
<name><surname>Li</surname><given-names>JD</given-names></name>
<etal></etal>
</person-group>
<article-title>Sp1 protein contributes to airway-specific rat MUC2 mucin gene transcription</article-title>
<source>Gene</source>
<year>1997</year>
<volume>198</volume>
<fpage>191</fpage>
<lpage>201</lpage>
</nlm-citation>
</ref>
<ref id="R33">
<label>33.</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name><surname>Kawano</surname><given-names>H</given-names></name>
<name><surname>Paparella</surname><given-names>MM</given-names></name>
<name><surname>Schachern</surname><given-names>PA</given-names></name>
<name><surname>Ho</surname><given-names>SB</given-names></name>
<name><surname>Lin</surname><given-names>J</given-names></name>
</person-group>
<article-title>Identification of MUC5B mucin gene in human middle ear with chronic otitis media</article-title>
<source>Laryngoscope</source>
<year>2000</year>
<volume>110</volume>
<fpage>668</fpage>
<lpage>73</lpage>
</nlm-citation>
</ref>
</ref-list>
<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption>
<p>Identification and quantitation of mucin or mucin-like glycoproteins in middle ear effusions of tumor necrosis factor (TNF)—<italic>α (B)</italic> and PBS-treated <italic>(A)</italic> rats. Fraction 9 had a high density of ∼1.42 g/mL and a hexose-to-protein ratio of ∼2:1. Levels of mucin or mucinlike glycoproteins in TNF-<italic>α</italic>—treated animals increased in a time-dependent manner (18h > 6h > lh), whereas those in controls did not. Each point represents averaged value of pooled middle ear effusions from 14 ears.</p>
</caption>
<graphic mimetype="image" xlink:href="182-3-882-fig001.tif"></graphic>
</fig>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption>
<p>Northern analysis of expression of mucin mRNA. <italic>A–E</italic>, Hybridization of blot with Muc1, Muc2, Muc3, Muc4, and Muc5ac mucin cDNA probes, respectively. RNA from middle ears treated with PBS or tumor necrosis factor (TNF)—<italic>α</italic> for 1 h (<italic>lanes 3</italic> and <italic>4</italic>), 6 h (<italic>lanes 5</italic> and <italic>6</italic>), and 18 h (<italic>lanes 7</italic> and <italic>8</italic>) demonstrated hybridizing signals for Muc2 but not for Muc1, Muc3, Muc4, or Muc5ac. <italic>Lane 1</italic>, Tracheal tissue, showing hybridizing signals for Muc2 or Muc5ac but not for Muc1, Muc3, or Muc4. <italic>Lane 2</italic>, Intestinal tissue, showing hybridizing signals for Muc2 and Muc3 but not for Muc1, Muc4, or Muc5ac. <italic>Lane 9</italic>, Negative control (human fibroblastic cells) with no hybridizing signals for Muc1, Muc2, Muc3, Muc4, or Muc5ac. Signals for Muc2 increased over time. Positions of rRNAs are indicated as size markers. Expression of gene for <italic>β</italic>-actin in same blot is shown at bottom, to indicate RNA amount loaded onto each lane.</p>
</caption>
<graphic mimetype="image" xlink:href="182-3-882-fig002.tif"></graphic>
</fig>
<fig id="F3" position="float">
<label>Figure 3</label>
<caption>
<p><italic>A</italic>, Expression of Muc2 mucin mRNA in middle ear after treatment with tumor necrosis factor (TNF)—<italic>α</italic> in dose-dependent manner by Northern analysis. <italic>Upper lanes 1–3</italic>, Hybridizing signals for Muc2 mRNA after TNF-<italic>α</italic> treatment at 0, 2.5, and 5 ng/<italic>µ</italic>L, respectively. Magnitude of increase was 2.5-fold at 2.5 ng/<italic>µ</italic>L and 5.1-fold at 5 ng/<italic>µ</italic>L, compared with that of controls <italic>(lane 1)</italic>, after normalization of data to expression of <italic>β</italic>-actin gene <italic>(lower lanes)</italic>. <italic>B</italic>, Actinomycin D (AD) inhibition of TNF-<italic>α</italic>—induced Muc2 mucin mRNA expression. <italic>Upper lane 2</italic>, Signal for Muc2 mucin gene 18 h after inoculation of 5 ng/<italic>µ</italic>L TNF-<italic>α</italic>. <italic>Lane 1</italic>, Control for <italic>lane 2. Lane 4</italic>, Inhibition by AD (6 <italic>µ</italic>g/mL) of signal for Muc2 mucin gene 18 h after inoculation of TNF-<italic>α</italic> (5 ng/<italic>µ</italic>L). <italic>Lane 3</italic>, Control for <italic>lane 4</italic>. Note that signals for <italic>β</italic>-actin gene were also inhibited <italic>(lower lanes 3</italic> and <italic>4)</italic>.</p>
</caption>
<graphic mimetype="image" xlink:href="182-3-882-fig003.tif"></graphic>
</fig>
<fig id="F4" position="float">
<label>Figure 4</label>
<caption>
<p>Quantitation of mRNA for endogenous tumor necrosis factor (TNF)—<italic>α</italic> gene in middle ear after treatment with exogenous TNF-<italic>α</italic> peptide. Upper panel represents expression of mRNA for TNF-<italic>α</italic> gene <italic>(lane 2)</italic>, compared with that of the control <italic>(lane 1)</italic>. <italic>Lane 3</italic>, omitting sample RNA, represents negative control for reverse transcription—polymerase chain reaction. Lower panels represent quantitation of mRNA for TNF-<italic>α</italic> gene. Decreasing concentrations of internal standard (IS) or control repetitive standard (CRS) were added to constant amount (1 <italic>µ</italic>g/microtube) of target sample (TS). Concentration of TNF-<italic>α</italic> mRNA from TNF-<italic>α</italic>—treated animals was equivalent to TNF-<italic>α</italic> CRS (0.16 <italic>µ</italic>g/mL). Concentration of TNF-<italic>α</italic> mRNA from controls was equivalent to RNA CRS for TNF-<italic>α</italic> (0.064 <italic>µ</italic>g/mL). Markers at left indicate competitive standard for RNA CRS and those at right indicate mRNA for TNF-<italic>α</italic> gene. <italic>Lane 1</italic>, Omission of murine leukemia virus reverse transcriptase; <italic>lane 2</italic>, omission of Taq polymerase; <italic>lane 9</italic>, omission of primers; <italic>lane 10</italic>, omission of samples (both RNA CRS and target RNA). No polymerase chain reaction products were found in <italic>lanes 1, 2, 9</italic>, or <italic>10</italic>.</p>
</caption>
<graphic mimetype="image" xlink:href="182-3-882-fig004.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn fn-type="financial-disclosure">
<p>Financial support: National Institutes of Health (DC-03433), Lions 5M multiple District Hearing Foundation, and National Organization for Hearing Research.</p>
</fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—α: Potential Cause for Mucoid Otitis Media</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—α: Potential Cause for Mucoid Otitis Media</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Jizhen</namePart><namePart type="family">Lin</namePart><affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</affiliation><affiliation>E-mail: linxx004@tc.umn.edu</affiliation><affiliation>Reprints or correspondence: Dr. Jizhen Lin, Room 216, Lions Research Bldg., 2001 6th St. SE, Minneapolis MN 55455 (linxx004@tc.umn.edu).</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Atsushi</namePart><namePart type="family">Haruta</namePart><affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hirokazu</namePart><namePart type="family">Kawano</namePart><affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Samuel B.</namePart><namePart type="family">Ho</namePart><affiliation>Otitis Media Research Center, Department of Medicine, Minneapolis, Minnesota</affiliation><affiliation>Otitis Media Research Center, Department of Veterans Affairs Medical Center, Minneapolis, Minnesota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">George L.</namePart><namePart type="family">Adams</namePart><affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Steven K.</namePart><namePart type="family">Juhn</namePart><affiliation>Otitis Media Research Center, Department of Otolaryngology, Minneapolis, Minnesota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Youngki</namePart><namePart type="family">Kim</namePart><affiliation>Otitis Media Research Center, Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2000-09</dateIssued><copyrightDate encoding="w3cdtf">2000</copyrightDate></originInfo><abstract>Mucoid otitis media (MOM) is characterized by viscous fluid, high in mucin concentration, which accumulates in the middle ear cavity. Recent studies suggest that initial infection in the middle ear cleft may be key to the development of MOM. However, factors of the initial infection attributed to the stimulation of mucin production are not clearly understood. This study demonstrated that tumor necrosis factor (TNF)—α, a proinflammatory cytokine in mucoid effusion, markedly increased Muc2 mucin mRNA expression in middle ear epithelium, in a time- and dose-dependent manner. Parallel to this was a marked increase in mucin glycoprotein in middle ear fluid. Also, TNF-α demonstrated an autocrine and/or paracrine effect on the expression of endogenous TNF-α gene in the middle ear, which may contribute to the production of mucin in this study. These findings suggest that TNF-α plays an important role in the development of MOM by stimulating mucin metabolism.</abstract><relatedItem type="host"><titleInfo><title>The Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>The Journal of Infectious Diseases</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>2000</date><detail type="volume"><caption>vol.</caption><number>182</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>882</start><end>887</end></extent></part></relatedItem><relatedItem type="references" displayLabel="R1"><titleInfo><title>A study of mucus glycoproteins in secretory otitis media</title></titleInfo><name type="personal"><namePart type="given">DT</namePart><namePart type="family">Brown</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Litt</namePart></name><name type="personal"><namePart type="given">WP</namePart><namePart type="family">Potsic</namePart></name><genre>journal</genre><note>BrownDT LittM PotsicWP A study of mucus glycoproteins in secretory otitis media Arch Otolaryngol 1985 111 688 95</note><relatedItem type="host"><titleInfo><title>Arch Otolaryngol</title></titleInfo><part><date>1985</date><detail type="volume"><caption>vol.</caption><number>111</number></detail><extent unit="pages"><start>688</start><end>95</end><list>688-95</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R2"><titleInfo><title>Otitis media with effusion: components which contribute to the viscous properties</title></titleInfo><name type="personal"><namePart type="given">S</namePart><namePart type="family">Carrie</namePart></name><name type="personal"><namePart type="given">DA</namePart><namePart type="family">Hutton</namePart></name><name type="personal"><namePart type="given">JP</namePart><namePart type="family">Birchall</namePart></name><name type="personal"><namePart type="given">GG</namePart><namePart type="family">Green</namePart></name><name type="personal"><namePart type="given">JP</namePart><namePart type="family">Pearson</namePart></name><genre>journal</genre><note>CarrieS HuttonDA BirchallJP GreenGG PearsonJP Otitis media with effusion: components which contribute to the viscous properties Acta Otolaryngol 1992 112 504 11</note><relatedItem type="host"><titleInfo><title>Acta Otolaryngol</title></titleInfo><part><date>1992</date><detail type="volume"><caption>vol.</caption><number>112</number></detail><extent unit="pages"><start>504</start><end>11</end><list>504-11</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R3"><titleInfo><title>Mucolytic agents and otitis media with effusion</title></titleInfo><name type="personal"><namePart type="given">JE</namePart><namePart type="family">FitzGerald</namePart></name><name type="personal"><namePart type="given">GG</namePart><namePart type="family">Green</namePart></name><name type="personal"><namePart type="given">JP</namePart><namePart type="family">Birchall</namePart></name><name type="personal"><namePart type="given">JP</namePart><namePart type="family">Pearson</namePart></name><genre>journal</genre><note>FitzGeraldJE GreenGG BirchallJP PearsonJP Mucolytic agents and otitis media with effusion Biomed Pharmacother 1988 42 505 11</note><relatedItem type="host"><titleInfo><title>Biomed Pharmacother</title></titleInfo><part><date>1988</date><detail type="volume"><caption>vol.</caption><number>42</number></detail><extent unit="pages"><start>505</start><end>11</end><list>505-11</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R4"><titleInfo><title>Vascular events in experimental otitis media models: a comparative study</title></titleInfo><name type="personal"><namePart type="given">P</namePart><namePart type="family">Goldie</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Hellstrom</namePart></name><name type="personal"><namePart type="given">U</namePart><namePart type="family">Johansson</namePart></name><genre>journal</genre><note>GoldieP HellstromS JohanssonU Vascular events in experimental otitis media models: a comparative study ORL J Otorhinolaryngol Relat Spec 1990 52 104 12</note><relatedItem type="host"><titleInfo><title>ORL J Otorhinolaryngol Relat Spec</title></titleInfo><part><date>1990</date><detail type="volume"><caption>vol.</caption><number>52</number></detail><extent unit="pages"><start>104</start><end>12</end><list>104-12</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R5"><titleInfo><title>The microbiology of serous and mucoid otitis media</title></titleInfo><name type="personal"><namePart type="given">GS</namePart><namePart type="family">Giebink</namePart></name><name type="personal"><namePart type="given">EL</namePart><namePart type="family">Mills</namePart></name><name type="personal"><namePart type="given">JS</namePart><namePart type="family">Huff</namePart></name><genre>journal</genre><note>GiebinkGS MillsEL HuffJS The microbiology of serous and mucoid otitis media Pediatrics 1979 63 915 9</note><relatedItem type="host"><titleInfo><title>Pediatrics</title></titleInfo><part><date>1979</date><detail type="volume"><caption>vol.</caption><number>63</number></detail><extent unit="pages"><start>915</start><end>9</end><list>915-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R6"><titleInfo><title>Immunologic characteristics of cytokines in otitis media with effusion</title></titleInfo><name type="personal"><namePart type="given">T</namePart><namePart type="family">Himi</namePart></name><name type="personal"><namePart type="given">T</namePart><namePart type="family">Suzuki</namePart></name><name type="personal"><namePart type="given">H</namePart><namePart type="family">Kodama</namePart></name><name type="personal"><namePart type="given">H</namePart><namePart type="family">Takezawa</namePart></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Kataura</namePart></name><genre>journal</genre><note>HimiT SuzukiT KodamaH TakezawaH KatauraA Immunologic characteristics of cytokines in otitis media with effusion Ann Otol Rhinol Laryngol Suppl 1992 157 21 5</note><relatedItem type="host"><titleInfo><title>Ann Otol Rhinol Laryngol Suppl</title></titleInfo><part><date>1992</date><detail type="volume"><caption>vol.</caption><number>157</number></detail><extent unit="pages"><start>21</start><end>5</end><list>21-5</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R7"><titleInfo><title>Increase of mucous glycoprotein secretion by tumor necrosis factor—α via a protein kinase C—dependent mechanism in cultured chinchilla middle ear epithelial cells</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Lin</namePart></name><name type="personal"><namePart type="given">Y</namePart><namePart type="family">Kim</namePart></name><name type="personal"><namePart type="given">SK</namePart><namePart type="family">Juhn</namePart></name><genre>journal</genre><note>LinJ KimY JuhnSK Increase of mucous glycoprotein secretion by tumor necrosis factor—α via a protein kinase C—dependent mechanism in cultured chinchilla middle ear epithelial cells Ann Otol Rhinol Laryngol 1998 107 213 9</note><relatedItem type="host"><titleInfo><title>Ann Otol Rhinol Laryngol</title></titleInfo><part><date>1998</date><detail type="volume"><caption>vol.</caption><number>107</number></detail><extent unit="pages"><start>213</start><end>9</end><list>213-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R8"><titleInfo><title>Mucin gene expression in the rat middle ear: an improved method for RNA harvest</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Lin</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Ho</namePart></name><name type="personal"><namePart type="given">L</namePart><namePart type="family">Schekels</namePart></name><name type="personal"><namePart type="given">MM</namePart><namePart type="family">Paparella</namePart></name><name type="personal"><namePart type="given">Y</namePart><namePart type="family">Kim</namePart></name><genre>journal</genre><note>LinJ HoS SchekelsL PaparellaMM KimY Mucin gene expression in the rat middle ear: an improved method for RNA harvest Ann Otol Rhinol Laryngol 1999 108 762 8</note><relatedItem type="host"><titleInfo><title>Ann Otol Rhinol Laryngol</title></titleInfo><part><date>1999</date><detail type="volume"><caption>vol.</caption><number>108</number></detail><extent unit="pages"><start>762</start><end>8</end><list>762-8</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R9"><titleInfo><title>Pneumococcus activation of the 5-lipoxygenase pathway and production of glycoproteins in the middle ear of rats</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Lin</namePart></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Vambutas</namePart></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Haruta</namePart></name><name type="personal"><namePart type="given">MM</namePart><namePart type="family">Paparella</namePart></name><name type="personal"><namePart type="given">GS</namePart><namePart type="family">Giebink</namePart></name><name type="personal"><namePart type="given">Y</namePart><namePart type="family">Kim</namePart></name><genre>journal</genre><note>LinJ VambutasA HarutaA PaparellaMM GiebinkGS KimY Pneumococcus activation of the 5-lipoxygenase pathway and production of glycoproteins in the middle ear of rats J Infect Dis 1999 179 1145 51</note><relatedItem type="host"><titleInfo><title>J Infect Dis</title></titleInfo><part><date>1999</date><detail type="volume"><caption>vol.</caption><number>179</number></detail><extent unit="pages"><start>1145</start><end>51</end><list>1145-51</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R10"><titleInfo><title>Cloning and characterization of mouse intestinal MUC3 mucin: 3′ sequence contains epidermalgrowth factor—like domains</title></titleInfo><name type="personal"><namePart type="given">LL</namePart><namePart type="family">Shekels</namePart></name><name type="personal"><namePart type="given">DA</namePart><namePart type="family">Hunninghake</namePart></name><name type="personal"><namePart type="given">AS</namePart><namePart type="family">Tisdale</namePart></name><genre>journal</genre><note>ShekelsLL HunninghakeDA TisdaleAS Cloning and characterization of mouse intestinal MUC3 mucin: 3′ sequence contains epidermalgrowth factor—like domains Biochem J 1998 330 1301 8</note><relatedItem type="host"><titleInfo><title>Biochem J</title></titleInfo><part><date>1998</date><detail type="volume"><caption>vol.</caption><number>330</number></detail><extent unit="pages"><start>1301</start><end>8</end><list>1301-8</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R11"><titleInfo><title>Molecular cloning and sequencing of the mucin subunit of a heterodimeric, bifunctional cell surface glycoprotein complex of ascites rat mammary adenocarcinoma cells</title></titleInfo><name type="personal"><namePart type="given">K</namePart><namePart type="family">Wu</namePart></name><name type="personal"><namePart type="given">N</namePart><namePart type="family">Fregien</namePart></name><name type="personal"><namePart type="given">KL</namePart><namePart type="family">Carraway</namePart></name><genre>journal</genre><note>WuK FregienN CarrawayKL Molecular cloning and sequencing of the mucin subunit of a heterodimeric, bifunctional cell surface glycoprotein complex of ascites rat mammary adenocarcinoma cells J Biol Chem 1994 269 11950 5</note><relatedItem type="host"><titleInfo><title>J Biol Chem</title></titleInfo><part><date>1994</date><detail type="volume"><caption>vol.</caption><number>269</number></detail><extent unit="pages"><start>11950</start><end>5</end><list>11950-5</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R12"><titleInfo><title>Mouse gastric mucin: cloning and chromosomal location</title></titleInfo><name type="personal"><namePart type="given">LL</namePart><namePart type="family">Shekels</namePart></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Lyftogt</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Kieliszewski</namePart></name><name type="personal"><namePart type="given">JD</namePart><namePart type="family">Filie</namePart></name><name type="personal"><namePart type="given">CA</namePart><namePart type="family">Kozak</namePart></name><name type="personal"><namePart type="given">SB</namePart><namePart type="family">Ho</namePart></name><genre>journal</genre><note>ShekelsLL LyftogtC KieliszewskiM FilieJD KozakCA HoSB Mouse gastric mucin: cloning and chromosomal location Biochem J 1995 311 775 85</note><relatedItem type="host"><titleInfo><title>Biochem J</title></titleInfo><part><date>1995</date><detail type="volume"><caption>vol.</caption><number>311</number></detail><extent unit="pages"><start>775</start><end>85</end><list>775-85</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R13"><titleInfo><title>Rat tumor necrosis factor—α: transcription in rat Kupffer cells and in vitro posttranscriptional processing based on a PCR-derived cDNA</title></titleInfo><name type="personal"><namePart type="given">HC</namePart><namePart type="family">Estler</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Grewe</namePart></name><name type="personal"><namePart type="given">R</namePart><namePart type="family">Gaussling</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Pavlovic</namePart></name><name type="personal"><namePart type="given">K</namePart><namePart type="family">Decker</namePart></name><genre>journal</genre><note>EstlerHC GreweM GausslingR PavlovicM DeckerK Rat tumor necrosis factor—α: transcription in rat Kupffer cells and in vitro posttranscriptional processing based on a PCR-derived cDNA Biol Chem Hoppe Seyler 1992 373 271 81</note><relatedItem type="host"><titleInfo><title>Biol Chem Hoppe Seyler</title></titleInfo><part><date>1992</date><detail type="volume"><caption>vol.</caption><number>373</number></detail><extent unit="pages"><start>271</start><end>81</end><list>271-81</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R14"><titleInfo><title>Quantitative RT-PCR for measuring gene expression</title></titleInfo><name type="personal"><namePart type="given">MC</namePart><namePart type="family">Riedy</namePart></name><name type="personal"><namePart type="given">EA</namePart><namePart type="family">Timm</namePart></name><name type="personal"><namePart type="given">CC</namePart><namePart type="family">Stewart</namePart></name><genre>journal</genre><note>RiedyMC TimmEA StewartCC Quantitative RT-PCR for measuring gene expression Biotechniques 1995 18 70 4</note><relatedItem type="host"><titleInfo><title>Biotechniques</title></titleInfo><part><date>1995</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><extent unit="pages"><start>70</start><end>4</end><list>70-4</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R15"><titleInfo><title>The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death</title></titleInfo><name type="personal"><namePart type="given">CA</namePart><namePart type="family">Smith</namePart></name><name type="personal"><namePart type="given">T</namePart><namePart type="family">Farrah</namePart></name><name type="personal"><namePart type="given">RG</namePart><namePart type="family">Goodwin</namePart></name><genre>journal</genre><note>SmithCA FarrahT GoodwinRG The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death Cell 1994 76 959 62</note><relatedItem type="host"><titleInfo><title>Cell</title></titleInfo><part><date>1994</date><detail type="volume"><caption>vol.</caption><number>76</number></detail><extent unit="pages"><start>959</start><end>62</end><list>959-62</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R16"><titleInfo><title>An endotoxin-induced serum factor that causes necrosis of tumors</title></titleInfo><name type="personal"><namePart type="given">EA</namePart><namePart type="family">Carswell</namePart></name><name type="personal"><namePart type="given">LJ</namePart><namePart type="family">Old</namePart></name><name type="personal"><namePart type="given">RL</namePart><namePart type="family">Kassel</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Green</namePart></name><name type="personal"><namePart type="given">N</namePart><namePart type="family">Fiore</namePart></name><name type="personal"><namePart type="given">B</namePart><namePart type="family">Williamson</namePart></name><genre>journal</genre><note>CarswellEA OldLJ KasselRL GreenS FioreN WilliamsonB An endotoxin-induced serum factor that causes necrosis of tumors Proc Natl Acad Sci USA 1975 72 3666 70</note><relatedItem type="host"><titleInfo><title>Proc Natl Acad Sci USA</title></titleInfo><part><date>1975</date><detail type="volume"><caption>vol.</caption><number>72</number></detail><extent unit="pages"><start>3666</start><end>70</end><list>3666-70</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R17"><titleInfo><title>Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytogenes infection</title></titleInfo><name type="personal"><namePart type="given">A</namePart><namePart type="family">Nakane</namePart></name><name type="personal"><namePart type="given">T</namePart><namePart type="family">Minagawa</namePart></name><name type="personal"><namePart type="given">K</namePart><namePart type="family">Kato</namePart></name><genre>journal</genre><note>NakaneA MinagawaT KatoK Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytogenes infection Infect Immun 1988 56 2563 9</note><relatedItem type="host"><titleInfo><title>Infect Immun</title></titleInfo><part><date>1988</date><detail type="volume"><caption>vol.</caption><number>56</number></detail><extent unit="pages"><start>2563</start><end>9</end><list>2563-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R18"><titleInfo><title>Contribution of tumor necrosis factor to host defense against staphylococci in a guinea pig model of foreign body infections</title></titleInfo><name type="personal"><namePart type="given">P</namePart><namePart type="family">Vaudaux</namePart></name><name type="personal"><namePart type="given">GE</namePart><namePart type="family">Grau</namePart></name><name type="personal"><namePart type="given">E</namePart><namePart type="family">Huggler</namePart></name><genre>journal</genre><note>VaudauxP GrauGE HugglerE Contribution of tumor necrosis factor to host defense against staphylococci in a guinea pig model of foreign body infections J Infect Dis 1992 166 58 64</note><relatedItem type="host"><titleInfo><title>J Infect Dis</title></titleInfo><part><date>1992</date><detail type="volume"><caption>vol.</caption><number>166</number></detail><extent unit="pages"><start>58</start><end>64</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R19"><titleInfo><title>Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia</title></titleInfo><name type="personal"><namePart type="given">KJ</namePart><namePart type="family">Tracey</namePart></name><name type="personal"><namePart type="given">Y</namePart><namePart type="family">Fong</namePart></name><name type="personal"><namePart type="given">DG</namePart><namePart type="family">Hesse</namePart></name><genre>journal</genre><note>TraceyKJ FongY HesseDG Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia Nature 1987 330 662 4</note><relatedItem type="host"><titleInfo><title>Nature</title></titleInfo><part><date>1987</date><detail type="volume"><caption>vol.</caption><number>330</number></detail><extent unit="pages"><start>662</start><end>4</end><list>662-4</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R20"><titleInfo><title>Tumors secreting human TNF/cachectin induce cachexia in mice</title></titleInfo><name type="personal"><namePart type="given">A</namePart><namePart type="family">Oliff</namePart></name><name type="personal"><namePart type="given">D</namePart><namePart type="family">Defeo-Jones</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Boyer</namePart></name><genre>journal</genre><note>OliffA Defeo-JonesD BoyerM Tumors secreting human TNF/cachectin induce cachexia in mice Cell 1987 50 555 63</note><relatedItem type="host"><titleInfo><title>Cell</title></titleInfo><part><date>1987</date><detail type="volume"><caption>vol.</caption><number>50</number></detail><extent unit="pages"><start>555</start><end>63</end><list>555-63</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R21"><titleInfo><title>Mice deficient for the 55-kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection</title></titleInfo><name type="personal"><namePart type="given">K</namePart><namePart type="family">Pfeffer</namePart></name><name type="personal"><namePart type="given">T</namePart><namePart type="family">Matsuyama</namePart></name><name type="personal"><namePart type="given">TM</namePart><namePart type="family">Kundig</namePart></name><genre>journal</genre><note>PfefferK MatsuyamaT KundigTM Mice deficient for the 55-kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection Cell 1993 73 457 67</note><relatedItem type="host"><titleInfo><title>Cell</title></titleInfo><part><date>1993</date><detail type="volume"><caption>vol.</caption><number>73</number></detail><extent unit="pages"><start>457</start><end>67</end><list>457-67</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R22"><titleInfo><title>Antiviral effects of recombinant tumor necrosis factor in vitro</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Mestan</namePart></name><name type="personal"><namePart type="given">W</namePart><namePart type="family">Digel</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Mittnacht</namePart></name><genre>journal</genre><note>MestanJ DigelW MittnachtS Antiviral effects of recombinant tumor necrosis factor in vitro Nature 1986 323 816 9</note><relatedItem type="host"><titleInfo><title>Nature</title></titleInfo><part><date>1986</date><detail type="volume"><caption>vol.</caption><number>323</number></detail><extent unit="pages"><start>816</start><end>9</end><list>816-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R23"><titleInfo><title>Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin-1</title></titleInfo><name type="personal"><namePart type="given">CA</namePart><namePart type="family">Dinarello</namePart></name><name type="personal"><namePart type="given">JG</namePart><namePart type="family">Cannon</namePart></name><name type="personal"><namePart type="given">SM</namePart><namePart type="family">Wolff</namePart></name><genre>journal</genre><note>DinarelloCA CannonJG WolffSM Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin-1 J Exp Med 1986 163 1433 50</note><relatedItem type="host"><titleInfo><title>J Exp Med</title></titleInfo><part><date>1986</date><detail type="volume"><caption>vol.</caption><number>163</number></detail><extent unit="pages"><start>1433</start><end>50</end><list>1433-50</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R24"><titleInfo><title>Tumour necrosis factor (cachectin) induces phospholipase A2 activity and synthesis of a phospholipase A2—activating protein in endothelial cells</title></titleInfo><name type="personal"><namePart type="given">MA</namePart><namePart type="family">Clark</namePart></name><name type="personal"><namePart type="given">MJ</namePart><namePart type="family">Chen</namePart></name><name type="personal"><namePart type="given">ST</namePart><namePart type="family">Crooke</namePart></name><name type="personal"><namePart type="given">JS</namePart><namePart type="family">Bomalaski</namePart></name><genre>journal</genre><note>ClarkMA ChenMJ CrookeST BomalaskiJS Tumour necrosis factor (cachectin) induces phospholipase A2 activity and synthesis of a phospholipase A2—activating protein in endothelial cells Biochem J 1988 250 125 32</note><relatedItem type="host"><titleInfo><title>Biochem J</title></titleInfo><part><date>1988</date><detail type="volume"><caption>vol.</caption><number>250</number></detail><extent unit="pages"><start>125</start><end>32</end><list>125-32</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R25"><titleInfo><title>TNF signal transduction and TNF-responsive genes</title></titleInfo><name type="personal"><namePart type="given">M</namePart><namePart type="family">Kronke</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Schutze</namePart></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Scheurich</namePart></name><name type="personal"><namePart type="given">K</namePart><namePart type="family">Pfizenmaier</namePart></name><name type="personal"><namePart type="given">BB</namePart><namePart type="family">Aggarwal</namePart></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Vilcek</namePart></name><genre>book</genre><note>KronkeM SchutzeS ScheurichP PfizenmaierK AggarwalBB VilcekJ TNF signal transduction and TNF-responsive genes Tumor necrosis factor: structure, function, and mechanism of action. Vol 56 1992 New York Marcel Dekker 189 216</note><relatedItem type="host"><titleInfo><title>Tumor necrosis factor: structure, function, and mechanism of action. Vol 56</title></titleInfo><originInfo><publisher>Marcel Dekker. </publisher><place><placeTerm type="text">New York</placeTerm></place></originInfo><part><date>1992</date><extent unit="pages"><start>189</start><end>216</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R26"><titleInfo><title>Tumor necrosis factor in the pathophysiology of infection and sepsis</title></titleInfo><name type="personal"><namePart type="given">Y</namePart><namePart type="family">Fong</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Lowry</namePart></name><genre>journal</genre><note>FongY LowryS Tumor necrosis factor in the pathophysiology of infection and sepsis Clin Immunol Immunopathol 1990 55 157 70</note><relatedItem type="host"><titleInfo><title>Clin Immunol Immunopathol</title></titleInfo><part><date>1990</date><detail type="volume"><caption>vol.</caption><number>55</number></detail><extent unit="pages"><start>157</start><end>70</end><list>157-70</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R27"><titleInfo><title>Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages</title></titleInfo><name type="personal"><namePart type="given">JL</namePart><namePart type="family">Urban</namePart></name><name type="personal"><namePart type="given">HM</namePart><namePart type="family">Shepard</namePart></name><name type="personal"><namePart type="given">JL</namePart><namePart type="family">Rothstein</namePart></name><name type="personal"><namePart type="given">BJ</namePart><namePart type="family">Sugarman</namePart></name><name type="personal"><namePart type="given">H</namePart><namePart type="family">Schreiber</namePart></name><genre>journal</genre><note>UrbanJL ShepardHM RothsteinJL SugarmanBJ SchreiberH Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages Proc Natl Acad Sci USA 1986 83 5233 7</note><relatedItem type="host"><titleInfo><title>Proc Natl Acad Sci USA</title></titleInfo><part><date>1986</date><detail type="volume"><caption>vol.</caption><number>83</number></detail><extent unit="pages"><start>5233</start><end>7</end><list>5233-7</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R28"><titleInfo><title>Endotoxin—cell membrane interactions leading to transmembrane signaling</title></titleInfo><name type="personal"><namePart type="given">DC</namePart><namePart type="family">Morrison</namePart></name><name type="personal"><namePart type="given">JA</namePart><namePart type="family">Rudbach</namePart></name><genre>journal</genre><note>MorrisonDC RudbachJA Endotoxin—cell membrane interactions leading to transmembrane signaling Contemp Top Mol Immunol 1981 8 187 218</note><relatedItem type="host"><titleInfo><title>Contemp Top Mol Immunol</title></titleInfo><part><date>1981</date><detail type="volume"><caption>vol.</caption><number>8</number></detail><extent unit="pages"><start>187</start><end>218</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R29"><titleInfo><title>The case for specific lipopolysaccharide receptors expressed on mammalian cells</title></titleInfo><name type="personal"><namePart type="given">DC</namePart><namePart type="family">Morrison</namePart></name><genre>journal</genre><note>MorrisonDC The case for specific lipopolysaccharide receptors expressed on mammalian cells Microb Pathog 1989 7 389 98</note><relatedItem type="host"><titleInfo><title>Microb Pathog</title></titleInfo><part><date>1989</date><detail type="volume"><caption>vol.</caption><number>7</number></detail><extent unit="pages"><start>389</start><end>98</end><list>389-98</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R30"><titleInfo><title>Bacteria and endotoxin in middle ear fluid and the course of secretory otitis media</title></titleInfo><name type="personal"><namePart type="given">T</namePart><namePart type="family">Ovesen</namePart></name><name type="personal"><namePart type="given">T</namePart><namePart type="family">Ledet</namePart></name><genre>journal</genre><note>OvesenT LedetT Bacteria and endotoxin in middle ear fluid and the course of secretory otitis media Clin Otolaryngol 1992 17 531 4</note><relatedItem type="host"><titleInfo><title>Clin Otolaryngol</title></titleInfo><part><date>1992</date><detail type="volume"><caption>vol.</caption><number>17</number></detail><extent unit="pages"><start>531</start><end>4</end><list>531-4</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R31"><titleInfo><title>Tumor necrosis factor—α induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells</title></titleInfo><name type="personal"><namePart type="given">SJ</namePart><namePart type="family">Levine</namePart></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Larivee</namePart></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Logun</namePart></name><name type="personal"><namePart type="given">CW</namePart><namePart type="family">Angus</namePart></name><name type="personal"><namePart type="given">FP</namePart><namePart type="family">Ognibene</namePart></name><name type="personal"><namePart type="given">JH</namePart><namePart type="family">Shelhamer</namePart></name><genre>journal</genre><note>LevineSJ LariveeP LogunC AngusCW OgnibeneFP ShelhamerJH Tumor necrosis factor—α induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells Am J Respir Cell Mol Biol 1995 12 196 204</note><relatedItem type="host"><titleInfo><title>Am J Respir Cell Mol Biol</title></titleInfo><part><date>1995</date><detail type="volume"><caption>vol.</caption><number>12</number></detail><extent unit="pages"><start>196</start><end>204</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R32"><titleInfo><title>Sp1 protein contributes to airway-specific rat MUC2 mucin gene transcription</title></titleInfo><name type="personal"><namePart type="given">H</namePart><namePart type="family">Nogami</namePart></name><name type="personal"><namePart type="given">H</namePart><namePart type="family">Ohmori</namePart></name><name type="personal"><namePart type="given">JD</namePart><namePart type="family">Li</namePart></name><genre>journal</genre><note>NogamiH OhmoriH LiJD Sp1 protein contributes to airway-specific rat MUC2 mucin gene transcription Gene 1997 198 191 201</note><relatedItem type="host"><titleInfo><title>Gene</title></titleInfo><part><date>1997</date><detail type="volume"><caption>vol.</caption><number>198</number></detail><extent unit="pages"><start>191</start><end>201</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R33"><titleInfo><title>Identification of MUC5B mucin gene in human middle ear with chronic otitis media</title></titleInfo><name type="personal"><namePart type="given">H</namePart><namePart type="family">Kawano</namePart></name><name type="personal"><namePart type="given">MM</namePart><namePart type="family">Paparella</namePart></name><name type="personal"><namePart type="given">PA</namePart><namePart type="family">Schachern</namePart></name><name type="personal"><namePart type="given">SB</namePart><namePart type="family">Ho</namePart></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Lin</namePart></name><genre>journal</genre><note>KawanoH PaparellaMM SchachernPA HoSB LinJ Identification of MUC5B mucin gene in human middle ear with chronic otitis media Laryngoscope 2000 110 668 73</note><relatedItem type="host"><titleInfo><title>Laryngoscope</title></titleInfo><part><date>2000</date><detail type="volume"><caption>vol.</caption><number>110</number></detail><extent unit="pages"><start>668</start><end>73</end><list>668-73</list></extent></part></relatedItem></relatedItem><identifier type="istex">8834A29A576FC54DF337614048EF5CA0F08063F5</identifier><identifier type="ark">ark:/67375/HXZ-XV76BB0D-F</identifier><identifier type="DOI">10.1086/315767</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2000 by the Infectious Diseases Society of America</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>Converted from (version 1.2.10) to MODS version 3.6.</recordOrigin><recordCreationDate encoding="w3cdtf">2020-04-17</recordCreationDate></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-XV76BB0D-F/record.json</uri></json:item></metadata><annexes><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-XV76BB0D-F/annexes.gif</uri></json:item><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-XV76BB0D-F/annexes.jpeg</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/MersV1/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001552 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 001552 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= MersV1
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:8834A29A576FC54DF337614048EF5CA0F08063F5
|texte= Induction of Mucin Gene Expression in Middle Ear of Rats by Tumor Necrosis Factor—α: Potential Cause for Mucoid Otitis Media
}}
| This area was generated with Dilib version V0.6.33. |  |