MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic -cell responses to the viral by-product double-stranded RNA
Identifieur interne : 001255 ( Istex/Corpus ); précédent : 001254; suivant : 001256MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic -cell responses to the viral by-product double-stranded RNA
Auteurs : Maikel L. Colli ; Fabrice Moore ; Esteban N. Gurzov ; Fernanda Ortis ; Decio L. EizirikSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-01-01.
Abstract
-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a dialog between -cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects -cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic -cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat -cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinicpolycitidilic acidPIC). Real-time RTPCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary -cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify -cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate -cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic -cell level.
Url:
DOI: 10.1093/hmg/ddp474
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Eizirik</name><affiliation><mods:affiliation>E-mail: deizirik@ulb.ac.be</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-01-01">2010-01-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="135">135</biblScope><biblScope unit="page" to="146">146</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">28418DE1F47D9807B102334B9C818D5C3D0C335A</idno><idno type="DOI">10.1093/hmg/ddp474</idno><idno type="ArticleID">ddp474</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a dialog between -cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects -cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic -cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat -cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinicpolycitidilic acidPIC). Real-time RTPCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary -cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify -cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate -cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic -cell level.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Maikel L. 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INS-1E cells and primary fluorescence-activated cell sorting-purified rat -cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinicpolycitidilic acidPIC). Real-time RTPCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary -cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify -cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. 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Published by Oxford University Press</p></availability><date>2009-10-13</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic -cell responses to the viral by-product double-stranded RNA</title><author xml:id="author-1"><persName><forename type="first">Maikel L.</forename><surname>Colli</surname></persName><affiliation>Laboratory of Experimental Medicine, Universit Libre de Bruxelles, B-1070 Brussels, Belgium</affiliation></author><author xml:id="author-2"><persName><forename type="first">Fabrice</forename><surname>Moore</surname></persName><affiliation>Laboratory of Experimental Medicine, Universit Libre de Bruxelles, B-1070 Brussels, Belgium</affiliation></author><author xml:id="author-3"><persName><forename type="first">Esteban N.</forename><surname>Gurzov</surname></persName><affiliation>Laboratory of Experimental Medicine, Universit Libre de Bruxelles, B-1070 Brussels, Belgium</affiliation></author><author xml:id="author-4"><persName><forename type="first">Fernanda</forename><surname>Ortis</surname></persName><affiliation>Laboratory of Experimental Medicine, Universit Libre de Bruxelles, B-1070 Brussels, Belgium</affiliation></author><author xml:id="author-5"><persName><forename type="first">Decio L.</forename><surname>Eizirik</surname></persName><email>deizirik@ulb.ac.be</email></author></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-01-01"></date><biblScope unit="volume">19</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="135">135</biblScope><biblScope unit="page" to="146">146</biblScope></imprint></monogr><idno type="istex">28418DE1F47D9807B102334B9C818D5C3D0C335A</idno><idno type="DOI">10.1093/hmg/ddp474</idno><idno type="ArticleID">ddp474</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009-10-13</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a dialog between -cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects -cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic -cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat -cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinicpolycitidilic acidPIC). Real-time RTPCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary -cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify -cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate -cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic -cell level.</p></abstract></profileDesc><revisionDesc><change when="2009-10-13">Created</change><change when="2010-01-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-10-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/28418DE1F47D9807B102334B9C818D5C3D0C335A/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</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="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddp474</article-id><article-id pub-id-type="publisher-id">ddp474</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic &bgr;-cell responses to the viral by-product double-stranded RNA</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Colli</surname><given-names>Maikel L.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Moore</surname><given-names>Fabrice</given-names></name></contrib><contrib contrib-type="author"><name><surname>Gurzov</surname><given-names>Esteban N.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Ortis</surname><given-names>Fernanda</given-names></name></contrib><contrib contrib-type="author"><name><surname>Eizirik</surname><given-names>Decio L.</given-names></name><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff><addr-line>Laboratory of Experimental Medicine</addr-line>, <institution>Université Libre de Bruxelles</institution>, <addr-line>B-1070 Brussels</addr-line>, <country>Belgium</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>Laboratory of Experimental Medicine</addr-line>, <institution>Université Libre de Bruxelles</institution>, <addr-line>Route de Lennik, 808, CP618, B-1070 Brussels</addr-line>, <country>Belgium</country>. Tel: <phone>+32 25556080</phone>; Fax: <fax>+32 25556239</fax>; Email: <email>deizirik@ulb.ac.be</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>1</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>13</day><month>10</month><year>2009</year></pub-date><volume>19</volume><issue>1</issue><fpage>135</fpage><lpage>146</lpage><history><date date-type="received"><day>20</day><month>7</month><year>2009</year></date><date date-type="accepted"><day>9</day><month>10</month><year>2009</year></date></history><copyright-statement>© The Author 2009. Published by Oxford University Press</copyright-statement><copyright-year>2010</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license><abstract><p>&bgr;-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a ‘dialog’ between &bgr;-cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects &bgr;-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic &bgr;-cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat &bgr;-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinic–polycitidilic acid—PIC). Real-time RT–PCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary &bgr;-cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify &bgr;-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate &bgr;-cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic &bgr;-cell level.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic -cell responses to the viral by-product double-stranded RNA</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic -cell responses to the viral by-product double-stranded RNA</title></titleInfo><name type="personal"><namePart type="given">Maikel L.</namePart><namePart type="family">Colli</namePart><affiliation>Laboratory of Experimental Medicine, Universit Libre de Bruxelles, B-1070 Brussels, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fabrice</namePart><namePart type="family">Moore</namePart><affiliation>Laboratory of Experimental Medicine, Universit Libre de Bruxelles, B-1070 Brussels, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Esteban N.</namePart><namePart type="family">Gurzov</namePart><affiliation>Laboratory of Experimental Medicine, Universit Libre de Bruxelles, B-1070 Brussels, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fernanda</namePart><namePart type="family">Ortis</namePart><affiliation>Laboratory of Experimental Medicine, Universit Libre de Bruxelles, B-1070 Brussels, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Decio L.</namePart><namePart type="family">Eizirik</namePart><affiliation>E-mail: deizirik@ulb.ac.be</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-01-01</dateIssued><dateCreated encoding="w3cdtf">2009-10-13</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a dialog between -cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects -cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic -cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat -cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinicpolycitidilic acidPIC). Real-time RTPCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary -cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify -cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate -cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic -cell level.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>19</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>135</start><end>146</end></extent></part></relatedItem><identifier type="istex">28418DE1F47D9807B102334B9C818D5C3D0C335A</identifier><identifier type="DOI">10.1093/hmg/ddp474</identifier><identifier type="ArticleID">ddp474</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2009. 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