Published online before print August 8, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0407256

Received for publication April 26, 2007.
Revised June 10, 2008.
Accepted for publication June 12, 2008.

Article

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

^@ To whom correspondence should be addressed. E-mail: pranoti.mandrekar{at}umassmed.edu.

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- 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 , a signaling intermediate of the LPS pathway, followed by IB degradation and increased NF-B activity, 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 • IKK

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