| Inhibition of hsp90 attenuates pro-inflammatory cytokines and prevents LPS induced liver injury. | |
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MedLine Citation:
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PMID: 22105779 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND: Endotoxin mediated pro-inflammatory cytokines play a significant role in pathogenesis of acute and chronic liver diseases. Hsp90 functions as an important chaperone of LPS signaling and is required for production of pro-inflammatory cytokines. We hypothesized that inhibition of hsp90 prevents LPS induced liver injury by decreasing pro-inflammatory cytokines. METHODS: C57BL/6 mice were injected i.p. with an hsp90 inhibitor, 17-DMAG, and LPS. Parameters of liver injury, pro-inflammatory cytokines, and mechanisms associated were studied by in vivo and in vitro experiments. RESULTS: Inhibition of hsp90 by 17-DMAG prevented LPS induced serum ALT and significantly reduced serum TNFα and IL-6 protein as well as mRNA in liver. Enhanced DNA binding activity of heat shock factor 1 (HSF1) and induction of target gene hsp70 confirmed hsp90 inhibition in liver. 17-DMAG treatment decreased CD14 mRNA and LPS induced NFκB DNA binding without affecting TLR4 mRNA in liver. Mechanistic studies revealed that 17-DMAG mediated inhibition of TNFα showed no effect on LPS induced NFκB promoter driven reporter activity but significantly decreased TNFα promoter driven reporter activity. Chromatin immunoprecipitation assays showed that 17-DMAG enhanced HSF1 binding to TNFα promoter, but not IL-6 promoter, suggesting HSF1 mediated direct inhibition of TNFα but not IL-6. We show that HSF1 indirectly regulates IL-6 via induction of another transcription factor, ATF3. Inhibition of HSF1 using siRNA prevented 17-DMAG mediated down-regulation of NFκB binding activity, TNFα and IL-6 induction supporting a repressive role for HSF1 on pro-inflammatory cytokine genes during hsp90 inhibition. CONCLUSION: Hsp90 inhibition in vivo reduces pro-inflammatory cytokines and prevents LPS induced liver injury likely via repressive action of HSF1. Our results suggest a novel application for 17-DMAG in alleviating LPS induced liver injury. (HEPATOLOGY 2011.). |
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Authors:
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Aditya Ambade; Donna Catalano; Arlene Lim; Pranoti Mandrekar |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-22 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: - ISSN: 1527-3350 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 American Association for the Study of Liver Diseases. |
Affiliation:
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Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605 United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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