title: Heme oxygenase-1 mediates the anti-inflammatory effects of acute alcohol on IL-10 induction involving p38 MAPK activation in monocytes.
abstract: Inflammation and immunoregulatory cytokines play a central role in alcohol-induced liver damage. We previously reported that acute alcohol treatment augments IL-10 and inhibits TNF-alpha production in monocytes. Heme oxygenase-1 (HO-1), a stress-inducible protein, also regulates IL-10 and TNF-alpha production. Here, we report that augmentation of LPS-induced IL-10 production by alcohol was prevented by inhibition of HO-1 activity. Acute ethanol increased LPS-induced enzyme activity and RNA levels of HO-1, and DNA binding of AP-1, a transcription factor essential in HO-1 regulation. LPS-induced phospho-p38 MAPK levels were augmented by ethanol treatment and the p38 inhibitor, SB203580, prevented both the ethanol-induced increase in IL-10 production and the inhibitory effect of ethanol on TNF-alpha production. Ethanol-induced down-regulation of TNF-alpha production was abrogated by inhibition of HO-1. We found that LPS-induced activation of NF-kappaB, a regulator of TNF-alpha, was inhibited by both ethanol treatment and HO-1 activation, but the ethanol-induced inhibition of NF-kappaB was HO-1 independent. In LPS-challenged mice in vivo, both acute alcohol administration and HO-1 activation augmented IL-10 and inhibited TNF-alpha serum levels. These results show that 1) acute alcohol augments HO-1 activation in monocytes, 2) HO-1 activation plays a role in alcohol-induced augmentation of IL-10 production likely via increased p38 MAPK activation, and 3) HO-1 activation is involved in attenuation of TNF-alpha production by alcohol independent of inhibition of NF-kappaB activation by alcohol. Thus, HO-1 activation is a key mediator of the anti-inflammatory effects of acute alcohol on monocytes.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Drechsler
authors.forename: Angela
authors.initials: A
authors.lastname: Dolganiuc
authors.forename: Oxana
authors.initials: O
authors.lastname: Norkina
authors.forename: Laszlo
authors.initials: L
authors.lastname: Romics
authors.forename: Weibo
authors.initials: W
authors.lastname: Li
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Fritz H
authors.initials: FH
authors.lastname: Bach
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016753:Interleukin-10; D000431:Ethanol; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases