Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease

Abstract

Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 295: G718 -G724, 2008. First published August 7, 2008 doi:10.1152/ajpgi.90232.2008.-Increased plasma and hepatic TNF-␣ expression is well documented in patients with alcoholic hepatitis and is implicated in the pathogenesis of alcoholic liver disease. We have previously shown that monocytes from patients with alcoholic hepatitis show increased constitutive and LPS-induced NF-B activation and TNF-␣ production. Our recent studies showed that chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes and Kupffer cells, leading to an increase in LPS-inducible TNF-␣ production by affecting NF-B activation and induction of TNF mRNA expression. Accordingly, the mechanisms underlying this ethanol-induced decrease in cellular cAMP leading to an increase in TNF expression were examined in monocytes/macrophages. In this study, chronic ethanol exposure was observed to significantly increase LPS-inducible expression of cAMP-specific phosphodiesterase (PDE)4B that degrades cellular cAMP. Increased PDE4B expression was associated with enhanced NF-B activation and transcriptional activity and subsequent priming of monocytes/macrophages leading to enhanced LPS-inducible TNF-␣ production. Selective inhibition of PDE4 by rolipram abrogated LPS-mediated TNF-␣ expression at both protein and mRNA levels in control and ethanol-treated cells. Notably, PDE4 inhibition did not affect LPS-inducible NF-B activation but significantly decreased NF-B transcriptional activity. These findings strongly support the pathogenic role of PDE4B in the ethanolmediated priming of monocytes/macrophages and increased LPSinducible TNF production and the subsequent development of alcoholic liver disease (ALD). Since enhanced TNF expression plays a significant role in the evolution of clinical and experimental ALD, its downregulation via selective PDE4B inhibitors could constitute a novel therapeutic approach in the treatment of ALD.DYSREGULATED TNF METABOLISM in alcoholic hepatitis (AH) was first described by us almost two decades ago with the observation that cultured monocytes from patients with AH spontaneously produced TNF and produced significantly more TNF in response to an LPS stimulus than control monocytes (20). Furthermore, we and others have shown that there are increased serum levels of TNF, increased monocyte TNF production, and hepatic immunohistochemical staining for TNF in AH that frequently correlate with disease severity and mortality (2,5,12,15,19,20,22,27). Although TNF plays an important role in the pathogenesis of liver injury and the clinical/biochemical abnormalities of AH (9, 20 -22), the mechanism(s) by which ethanol enhances TNF expression, particularly in monocytes/macrophages, is only beginning to be understood (6,14,37,38). We recently demonstrated that chronic ethanol exposure of monocytes/macropha...

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