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dc.contributor.authorAmbade, Aditya
dc.contributor.authorCatalano, Donna
dc.contributor.authorLim, Arlene
dc.contributor.authorMandrekar, Pranoti
dc.date2022-08-11T08:11:05.000
dc.date.accessioned2022-08-23T17:32:38Z
dc.date.available2022-08-23T17:32:38Z
dc.date.issued2012-05-01
dc.date.submitted2012-06-22
dc.identifier.citation<p>Hepatology. 2012 May;55(5):1585-95. doi: 10.1002/hep.24802. Epub 2012 Mar 18. <a href="http://dx.doi.org/10.1002/hep.24802">Link to article on publisher's site</a></p>
dc.identifier.issn0270-9139 (Linking)
dc.identifier.doi10.1002/hep.24802
dc.identifier.pmid22105779
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50993
dc.description.abstractEndotoxin-mediated proinflammatory cytokines play a significant role in the pathogenesis of acute and chronic liver diseases. Heat shock protein 90 (molecular weight, 90 kDa) (hsp90) functions as an important chaperone of lipopolysaccharide (LPS) signaling and is required for the production of proinflammatory cytokines. We hypothesized that inhibition of hsp90 would prevent LPS-induced liver injury by decreasing proinflammatory cytokines. C57BL/6 mice were injected intraperitoneally with an hsp90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), and LPS. Parameters of liver injury, proinflammatory cytokines, and associated mechanisms were studied by in vivo and in vitro experiments. Inhibition of hsp90 by 17-DMAG prevented LPS-induced increases in serum alanine aminotransferase activity and significantly reduced serum tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) protein as well as messenger RNA (mRNA) in liver. Enhanced DNA-binding activity of heat shock transcription factor 1 (HSF1) and induction of target gene heat shock protein 70 (molecular weight, 70 kDa) confirmed hsp90 inhibition in liver. 17-DMAG treatment decreased cluster of differentiation 14 mRNA and LPS-induced nuclear factor kappa light-chain enhancer of activated B cells (NFkappaB) DNA binding without affecting Toll-like receptor 4 mRNA in liver. Mechanistic studies revealed that 17-DMAG-mediated inhibition of TNFalpha showed no effect on LPS-induced NFkappaB promoter-driven reporter activity, but significantly decreased TNFalpha promoter-driven reporter activity. Chromatin immunoprecipitation assays showed that 17-DMAG enhanced HSF1 binding to the TNFalpha promoter, but not the IL-6 promoter, suggesting HSF1 mediated direct inhibition of TNFalpha, but not IL-6. We show that HSF1 indirectly regulates IL-6 by the induction of another transcription factor, activating transcription factor 3. Inhibition of HSF1, using small interfering RNA, prevented 17-DMAG-mediated down-regulation of NFkappaB-binding activity, TNFalpha, and IL-6 induction, supporting a repressive role for HSF1 on proinflammatory cytokine genes during hsp90 inhibition. CONCLUSION: Hsp90 inhibition in vivo reduces proinflammatory cytokines and prevents LPS-induced liver injury likely through repressive action of HSF1. Our results suggest a novel application for 17-DMAG in alleviating LPS-induced liver injury.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=22105779&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342823/
dc.subjectBenzoquinones
dc.subjectCytokines
dc.subjectDNA-Binding Proteins
dc.subjectHSP90 Heat-Shock Proteins
dc.subjectLactams, Macrocyclic
dc.subjectLiver
dc.subjectLiver Diseases
dc.subjectDigestive System Diseases
dc.subjectGastroenterology
dc.subjectHepatology
dc.subjectPhysiology
dc.titleInhibition of heat shock protein (molecular weight 90 kDa) attenuates proinflammatory cytokines and prevents lipopolysaccharide-induced liver injury in mice
dc.typeJournal Article
dc.source.journaltitleHepatology (Baltimore, Md.)
dc.source.volume55
dc.source.issue5
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/wfc_pp/528
dc.identifier.contextkey3017585
html.description.abstract<p>Endotoxin-mediated proinflammatory cytokines play a significant role in the pathogenesis of acute and chronic liver diseases. Heat shock protein 90 (molecular weight, 90 kDa) (hsp90) functions as an important chaperone of lipopolysaccharide (LPS) signaling and is required for the production of proinflammatory cytokines. We hypothesized that inhibition of hsp90 would prevent LPS-induced liver injury by decreasing proinflammatory cytokines. C57BL/6 mice were injected intraperitoneally with an hsp90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), and LPS. Parameters of liver injury, proinflammatory cytokines, and associated mechanisms were studied by in vivo and in vitro experiments. Inhibition of hsp90 by 17-DMAG prevented LPS-induced increases in serum alanine aminotransferase activity and significantly reduced serum tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) protein as well as messenger RNA (mRNA) in liver. Enhanced DNA-binding activity of heat shock transcription factor 1 (HSF1) and induction of target gene heat shock protein 70 (molecular weight, 70 kDa) confirmed hsp90 inhibition in liver. 17-DMAG treatment decreased cluster of differentiation 14 mRNA and LPS-induced nuclear factor kappa light-chain enhancer of activated B cells (NFkappaB) DNA binding without affecting Toll-like receptor 4 mRNA in liver. Mechanistic studies revealed that 17-DMAG-mediated inhibition of TNFalpha showed no effect on LPS-induced NFkappaB promoter-driven reporter activity, but significantly decreased TNFalpha promoter-driven reporter activity. Chromatin immunoprecipitation assays showed that 17-DMAG enhanced HSF1 binding to the TNFalpha promoter, but not the IL-6 promoter, suggesting HSF1 mediated direct inhibition of TNFalpha, but not IL-6. We show that HSF1 indirectly regulates IL-6 by the induction of another transcription factor, activating transcription factor 3. Inhibition of HSF1, using small interfering RNA, prevented 17-DMAG-mediated down-regulation of NFkappaB-binding activity, TNFalpha, and IL-6 induction, supporting a repressive role for HSF1 on proinflammatory cytokine genes during hsp90 inhibition.</p> <p>CONCLUSION: Hsp90 inhibition in vivo reduces proinflammatory cytokines and prevents LPS-induced liver injury likely through repressive action of HSF1. Our results suggest a novel application for 17-DMAG in alleviating LPS-induced liver injury.</p>
dc.identifier.submissionpathwfc_pp/528
dc.contributor.departmentDepartment of Medicine, Division of Gastroenterology
dc.source.pages1585-95


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