title: Alcohol exposure regulates heat shock transcription factor binding and heat shock proteins 70 and 90 in monocytes and macrophages: implication for TNF-alpha regulation.
abstract: Immunomodulatory effects of alcohol use involve regulation of innate immune cell function leading to liver disease. Alteration of inflammatory responses by alcohol is linked to dysregulated TNF-alpha production. Alcohol-induced oxidative stress also contributes to alterations in inflammatory cell activity. Heat shock proteins (hsps) and the heat shock transcription factor-1 (HSF-1) induced by oxidative stress regulate NF-kappaB activation and TNF-alpha gene expression in monocytes and macrophages. Here, we report that in vitro alcohol treatment induced and augmented LPS-induced HSF-1 nuclear translocation and DNA-binding activity in monocytes and macrophages. Supershift analysis revealed that alcohol regulated HSF-1- and not HSF-2-binding activity. Hsp70, a target gene induced by HSF-1, was transiently increased within 24 h by alcohol, but extended alcohol exposure decreased hsp70 in macrophages. The alcohol-induced alteration of hsp70 correlated with a concomitant change in hsp70 promoter activity. Hsp90, another HSF-1 target gene, was decreased during short-term alcohol but increased after prolonged alcohol exposure. Decreased hsp90-HSF-1 complexes after short-term alcohol indicated dissociation of HSF-1 from hsp90. On the other hand, hsp90 interacted with client protein IkappaB kinase beta, a signaling intermediate of the LPS pathway, followed by IkappaBalpha degradation and increased NF-kappaB activity after chronic alcohol exposure, indicating that hsp90 plays an important role in supporting inflammatory cytokine production. Inhibition of hsp90 using geldanamycin prevented prolonged alcohol-induced elevation in LPS-induced NF-kappaB and TNF-alpha production. These results suggest that alcohol exposure differentially regulates hsp70 and hsp90 via HSF-1 activation. Further, hsp90 regulates TNF-alpha production in macrophages contributing to alcohol-induced inflammation.
authors.affiliation: Department of Medicine, University of Massachusetts Medical Center, Worcester, Massachusetts 01605, USA. pranoti.mandrekar@umassmed.edu
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Valentina
authors.initials: V
authors.lastname: Jeliazkova
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
mesh_terms: D000818:Animals; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000494:pharmacology*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D012313:RNA