Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP‐1 cell neurotoxicity
Identifieur interne : 002285 ( Main/Exploration ); précédent : 002284; suivant : 002286Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP‐1 cell neurotoxicity
Auteurs : Andis Klegeris [Canada] ; Jane Li [États-Unis] ; Theo K. Bammler [États-Unis] ; Jinghua Jin [États-Unis] ; David Zhu [États-Unis] ; Daniel T. Kashima [États-Unis] ; Sheng Pan [États-Unis] ; Sadayuki Hashioka [Canada] ; John Maguire [Canada] ; Patrick L. Mcgeer [Canada] ; Jing Zhang [États-Unis]Source :
- Glia [ 0894-1491 ] ; 2008-04-15.
English descriptors
- KwdEn :
- Alzheimer disease, Analysis of Variance, Arginine, Carbon Isotopes, Cell Line, Computational Biology (methods), Dose-Response Relationship, Drug, Drug Interactions, Enzyme Inhibitors (pharmacology), Enzyme-Linked Immunosorbent Assay, Humans, Interferon-gamma (pharmacology), L-Lactate Dehydrogenase (metabolism), Lipopolysaccharides (pharmacology), Mass Spectrometry, Microglia (drug effects), Microglia (enzymology), Monocytes (drug effects), Monocytes (enzymology), Neuroblastoma, Neurotoxins (antagonists & inhibitors), Neurotoxins (pharmacology), Parkinson disease, Serine Endopeptidases (metabolism), Tetrazolium Salts, Thiazoles, mass spectrometry, neuroinflammation, proteomics.
- MESH :
- chemical , antagonists & inhibitors : Neurotoxins.
- chemical , metabolism : L-Lactate Dehydrogenase, Serine Endopeptidases.
- chemical , pharmacology : Enzyme Inhibitors, Interferon-gamma, Lipopolysaccharides, Neurotoxins.
- chemical : Arginine, Carbon Isotopes, Tetrazolium Salts, Thiazoles.
- drug effects : Microglia, Monocytes.
- enzymology : Microglia, Monocytes.
- methods : Computational Biology.
- Analysis of Variance, Cell Line, Dose-Response Relationship, Drug, Drug Interactions, Enzyme-Linked Immunosorbent Assay, Humans, Mass Spectrometry, Neuroblastoma.
Abstract
Reactive microglial cells may exacerbate the pathology in some neurodegenerative disorders. Supernatants of stimulated human microglial cells, or their surrogate THP‐1 cells, are lethal to cultured human neuroblastoma SH‐SY5Y cells. To explore this neurotoxicity, we examined the spectrum of proteins generated by THP‐1 cells using the technique of stable isotope labeling by amino acids in cell culture (SILAC). Unstimulated cells were grown in medium with light L‐[12C6] arginine while cells stimulated by lipopolysaccharide (LPS) plus interferon‐γ (IFN‐γ) were grown in medium with heavy L‐[13C6] arginine. Proteins isolated from the media were digested with trypsin, and relative concentrations of generated peptides determined by mass spectrometry. More than 1,500 proteins or putative proteins were identified. Of these, 174 were increased and 189 decreased by more than twofold in the stimulated cell supernatant. We selected one upregulated protein, prolyl endopeptidase (PEP), for further investigation of its potential contribution to neurotoxicity. We first confirmed its upregulation by comparing its enzymatic activity in stimulated and unstimulated cell supernatants. We then evaluated two specific PEP inhibitors, Boc‐Asn‐Phe‐Pro‐aldehyde and Z‐Pro‐Pro‐aldehyde‐dimethyl acetal, for their potential to reduce toxicity of stimulated THP‐1 cell and human microglia supernatants towards SH‐SY5Y cells. We found both to be partially protective in a concentration‐dependent manner. Inhibition of PEP may be a therapeutic approach to neurodegenerative disorders including Alzheimer and Parkinson diseases. © 2008 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/glia.20645
Affiliations:
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Mcgeer</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC V6T 1Z3</wicri:regionArea><wicri:noRegion>BC V6T 1Z3</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Washington (État)</region></placeName><wicri:cityArea>Division of Neuropathology, Harborview Medical Center, University of Washington School of Medicine, Seattle</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j">Glia</title><title level="j" type="abbrev">Glia</title><idno type="ISSN">0894-1491</idno><idno type="eISSN">1098-1136</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2008-04-15">2008-04-15</date><biblScope unit="volume">56</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="675">675</biblScope><biblScope unit="page" to="685">685</biblScope></imprint><idno type="ISSN">0894-1491</idno></series><idno type="istex">63A2D272D94F4D87F840566897F2A2FD803C617D</idno><idno type="DOI">10.1002/glia.20645</idno><idno type="ArticleID">GLIA20645</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0894-1491</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alzheimer disease</term><term>Analysis of Variance</term><term>Arginine</term><term>Carbon Isotopes</term><term>Cell Line</term><term>Computational Biology (methods)</term><term>Dose-Response Relationship, Drug</term><term>Drug Interactions</term><term>Enzyme Inhibitors (pharmacology)</term><term>Enzyme-Linked Immunosorbent Assay</term><term>Humans</term><term>Interferon-gamma (pharmacology)</term><term>L-Lactate Dehydrogenase (metabolism)</term><term>Lipopolysaccharides (pharmacology)</term><term>Mass Spectrometry</term><term>Microglia (drug effects)</term><term>Microglia (enzymology)</term><term>Monocytes (drug effects)</term><term>Monocytes (enzymology)</term><term>Neuroblastoma</term><term>Neurotoxins (antagonists & inhibitors)</term><term>Neurotoxins (pharmacology)</term><term>Parkinson disease</term><term>Serine Endopeptidases (metabolism)</term><term>Tetrazolium Salts</term><term>Thiazoles</term><term>mass spectrometry</term><term>neuroinflammation</term><term>proteomics</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Neurotoxins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>L-Lactate Dehydrogenase</term><term>Serine Endopeptidases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term><term>Interferon-gamma</term><term>Lipopolysaccharides</term><term>Neurotoxins</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Arginine</term><term>Carbon Isotopes</term><term>Tetrazolium Salts</term><term>Thiazoles</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Microglia</term><term>Monocytes</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Microglia</term><term>Monocytes</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Computational Biology</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Analysis of Variance</term><term>Cell Line</term><term>Dose-Response Relationship, Drug</term><term>Drug Interactions</term><term>Enzyme-Linked Immunosorbent Assay</term><term>Humans</term><term>Mass Spectrometry</term><term>Neuroblastoma</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Reactive microglial cells may exacerbate the pathology in some neurodegenerative disorders. Supernatants of stimulated human microglial cells, or their surrogate THP‐1 cells, are lethal to cultured human neuroblastoma SH‐SY5Y cells. To explore this neurotoxicity, we examined the spectrum of proteins generated by THP‐1 cells using the technique of stable isotope labeling by amino acids in cell culture (SILAC). Unstimulated cells were grown in medium with light L‐[12C6] arginine while cells stimulated by lipopolysaccharide (LPS) plus interferon‐γ (IFN‐γ) were grown in medium with heavy L‐[13C6] arginine. Proteins isolated from the media were digested with trypsin, and relative concentrations of generated peptides determined by mass spectrometry. More than 1,500 proteins or putative proteins were identified. Of these, 174 were increased and 189 decreased by more than twofold in the stimulated cell supernatant. We selected one upregulated protein, prolyl endopeptidase (PEP), for further investigation of its potential contribution to neurotoxicity. We first confirmed its upregulation by comparing its enzymatic activity in stimulated and unstimulated cell supernatants. We then evaluated two specific PEP inhibitors, Boc‐Asn‐Phe‐Pro‐aldehyde and Z‐Pro‐Pro‐aldehyde‐dimethyl acetal, for their potential to reduce toxicity of stimulated THP‐1 cell and human microglia supernatants towards SH‐SY5Y cells. We found both to be partially protective in a concentration‐dependent manner. Inhibition of PEP may be a therapeutic approach to neurodegenerative disorders including Alzheimer and Parkinson diseases. © 2008 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Washington (État)</li></region></list><tree><country name="Canada"><noRegion><name sortKey="Klegeris, Andis" sort="Klegeris, Andis" uniqKey="Klegeris A" first="Andis" last="Klegeris">Andis Klegeris</name></noRegion><name sortKey="Hashioka, Sadayuki" sort="Hashioka, Sadayuki" uniqKey="Hashioka S" first="Sadayuki" last="Hashioka">Sadayuki Hashioka</name><name sortKey="Maguire, John" sort="Maguire, John" uniqKey="Maguire J" first="John" last="Maguire">John Maguire</name><name sortKey="Mcgeer, Patrick L" sort="Mcgeer, Patrick L" uniqKey="Mcgeer P" first="Patrick L." last="Mcgeer">Patrick L. Mcgeer</name><name sortKey="Mcgeer, Patrick L" sort="Mcgeer, Patrick L" uniqKey="Mcgeer P" first="Patrick L." last="Mcgeer">Patrick L. Mcgeer</name></country><country name="États-Unis"><region name="Washington (État)"><name sortKey="Li, Jane" sort="Li, Jane" uniqKey="Li J" first="Jane" last="Li">Jane Li</name></region><name sortKey="Bammler, Theo K" sort="Bammler, Theo K" uniqKey="Bammler T" first="Theo K." last="Bammler">Theo K. Bammler</name><name sortKey="Jin, Jinghua" sort="Jin, Jinghua" uniqKey="Jin J" first="Jinghua" last="Jin">Jinghua Jin</name><name sortKey="Kashima, Daniel T" sort="Kashima, Daniel T" uniqKey="Kashima D" first="Daniel T." last="Kashima">Daniel T. Kashima</name><name sortKey="Pan, Sheng" sort="Pan, Sheng" uniqKey="Pan S" first="Sheng" last="Pan">Sheng Pan</name><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name><name sortKey="Zhu, David" sort="Zhu, David" uniqKey="Zhu D" first="David" last="Zhu">David Zhu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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