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Heat shock protein 90 inhibition in murine macrophages prevents chronic alcohol induced TNF‐α production
Author(s) -
Dotson Dominique,
Ambade Aditya Ambade,
Catalano Donna,
Mandrekar Pranoti
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1116.3
Subject(s) - heat shock protein , tumor necrosis factor alpha , hsp70 , chemistry , macrophage , medicine , microbiology and biotechnology , immunology , biology , biochemistry , in vitro , gene
Activation of toll‐like receptor 4 (TLR‐4) signaling on Kupffer cells is an important mediator of alcoholic liver disease. Chronic alcohol induced oxidative stress regulates heat shock protein 70 and 90 via HSF‐1 activation in the liver. While hsp70 inhibits TLR4 signaling, hsp90 chaperones TLR4/CD14 receptor complex and its down‐stream signaling molecules to regulate inflammatory cytokine TNF‐α production in macrophages. It was hypothesized that the inhibition of hsp90 would decrease the inflammatory cytokine TNF‐α and likely alleviates alcoholic liver injury. To test this hypothesis, murine macrophages RAW 264.7 were exposed to chronic alcohol at various concentrations and subsequently treated with 17‐DMAG in the presence or absence of lipopolysaccharide (LPS). At the end of the six hour exposure, samples were analyzed for TNF‐α. Total RNA was extracted at an earlier time point and analyzed for hsp70, which increased in cells treated with hsp90 inhibitors. Flow cytometry data show no significant alterations in surface expression of CD14 and TLR4 after inhibition of hsp90 chronic alcohol exposure. The results suggest that chronic alcohol exposure in RAW264.7 macrophages decreases TNF‐α by inhibiting hsp90. Thus, these studies reveal hsp90 as a likely target to modulate inflammatory responses and alleviate alcoholic liver injury. Supported by NIH 5T34GM008411 and NIAAA/NIH RO1AA017986