Published online before print August 8, 2008

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(Journal of Leukocyte Biology. 2008;84:1335-1345.)
© 2008 by Society for Leukocyte Biology

Alcohol exposure regulates heat shock transcription factor binding and heat shock proteins 70 and 90 in monocytes and macrophages: implication for TNF- regulation

Department of Medicine, University of Massachusetts Medical Center, Worcester, Massachusetts, USA

¹ Correspondence: Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Worcester, MA 01605, USA. E-mail: pranoti.mandrekar{at}umassmed.edu

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- 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-B activation and TNF- 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 IB kinase β, a signaling intermediate of the LPS pathway, followed by IB degradation and increased NF-B 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-B and TNF- production. These results suggest that alcohol exposure differentially regulates hsp70 and hsp90 via HSF-1 activation. Further, hsp90 regulates TNF- production in macrophages contributing to alcohol-induced inflammation.

Key Words: HSF-1 • ethanol • hsp70 • hsp 90 • IKKβ

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