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HORMONES AND SIGNALING

Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-B activity and TNF expression: relevance to alcoholic liver disease

¹Department of Internal Medicine and ²Department of Pharmacology and Toxicology, University of Louisville Medical Center, and ³Louisville Department of Veterans Affairs Medical Center, Louisville, Kentucky

Submitted 1 March 2006 ; accepted in final form 28 May 2006

Increased plasma and hepatic TNF- 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-B activation and TNF- production. Studies in monocytes have shown that cAMP plays an important role in regulating TNF- expression, and elevation of cellular cAMP suppresses TNF- 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- production by affecting NF-B 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- expression in ethanol-treated cells. Importantly, cAMP did not affect LPS-inducible NF-B 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.

alcohol; Kupffer cells; dibutyryl cAMP

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