title: Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-kappaB activity and TNF expression: relevance to alcoholic liver disease.
abstract: Increased plasma and hepatic TNF-alpha activity has been implicated in the pathogenesis of alcoholic liver disease (ALD). We previously reported that monocytes from alcoholic patients show enhanced constitutive as well as LPS-inducible NF-kappaB activation and TNF-alpha production. Studies in monocytes have shown that cAMP plays an important role in regulating TNF-alpha expression, and elevation of cellular cAMP suppresses TNF-alpha production. The effects of chronic ethanol exposure on the cellular levels of cAMP as well as TNF expression in monocytes were examined in vitro and in rat primary hepatic Kupffer cells obtained from a clinically relevant enteral alcohol feeding model of ALD. Chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes. Consistent with the decrease in cAMP levels, ethanol led to an increase in LPS-inducible TNF-alpha production by affecting NF-kappaB activation and induction of TNF mRNA expression, without any change in TNF mRNA stability. Enhancement of cellular cAMP with dibutyryl cAMP abrogated LPS-mediated TNF-alpha expression in ethanol-treated cells. Importantly, cAMP did not affect LPS-inducible NF-kappaB activation but significantly decreased its transcriptional activity. Together, these data strongly suggest that ethanol can synergize with LPS to upregulate the induction of TNF gene expression and consequent TNF overproduction by decreasing the cellular cAMP levels in monocytes/macrophages. Furthermore, these data also support the notion that cAMP-elevating agents could constitute an effective therapeutic approach in attenuating or preventing the progression of liver disease in alcoholic patients.
authors.affiliation: Dept. of Medicine, Pharmacology and Toxicology, Univ. of Louisville Medical Center, 550 S. Jackson St., ACB 3rd Floor, Louisville, KY 40292, USA. craig.mcclain@louisville.edu
authors.forename: Leila
authors.initials: L
authors.lastname: Gobejishvili
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
authors.forename: Swati
authors.initials: S
authors.lastname: Joshi-Barve
authors.forename: Silvia
authors.initials: S
authors.lastname: Uriarte
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
authors.forename: Craig
authors.initials: C
authors.lastname: McClain
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D000242:Cyclic AMP