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    Inhibition of heat shock protein (molecular weight 90 kDa) attenuates proinflammatory cytokines and prevents lipopolysaccharide-induced liver injury in mice

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    Authors
    Ambade, Aditya
    Catalano, Donna
    Lim, Arlene
    Mandrekar, Pranoti
    UMass Chan Affiliations
    Department of Medicine, Division of Gastroenterology
    Document Type
    Journal Article
    Publication Date
    2012-05-01
    Keywords
    Benzoquinones
    Cytokines
    DNA-Binding Proteins
    HSP90 Heat-Shock Proteins
    Lactams, Macrocyclic
    Liver
    Liver Diseases
    Digestive System Diseases
    Gastroenterology
    Hepatology
    Physiology
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    Link to Full Text
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342823/
    Abstract
    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. 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.
    Source

    Hepatology. 2012 May;55(5):1585-95. doi: 10.1002/hep.24802. Epub 2012 Mar 18. Link to article on publisher's site

    DOI
    10.1002/hep.24802
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/50993
    PubMed ID
    22105779
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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1002/hep.24802
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