Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease
Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease
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DOI：
10.1152/ajpgi.90232.2008
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发表时间：
2008-10-01
影响因子：
4.5
通讯作者：
McClain, Craig
中科院分区：
文献类型：
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作者：
Gobejishvili, Leila;Barve, Shirish;McClain, Craig
酒精性肝炎患者血浆和肝脏TNF-α表达增加已被充分证实，并与酒精性肝病的发病机制有关。我们先前已经证明，酒精性肝炎患者的单核细胞表现出增加的组成性和LPS诱导的NF-κ B活化和TNF-α产生。我们最近的研究表明，慢性乙醇暴露显着降低细胞cAMP水平在LPS刺激和未刺激的单核细胞和枯否细胞，导致增加LPS诱导的TNF-α的生产，通过影响NF-κ B激活和诱导TNF mRNA的表达。因此，在单核细胞/巨噬细胞中检查了这种乙醇诱导的细胞cAMP减少导致TNF表达增加的机制。在这项研究中，观察到慢性乙醇暴露显着增加LPS诱导的cAMP特异性磷酸二酯酶（PDE）4 B的表达，降解细胞cAMP。PDE 4 B表达增加与NF-κ B活化和转录活性增强以及随后单核细胞/巨噬细胞引发相关，导致LPS诱导的TNF-α产生增强。咯利普兰选择性抑制PDE 4在对照和乙醇处理的细胞中在蛋白质和mRNA水平上废除了LPS介导的TNF-α表达。值得注意的是，PDE 4抑制不影响LPS诱导的NF-κ B活化，但显著降低NF-κ B转录活性。这些发现强烈支持PDE 4 B在乙醇介导的单核细胞/巨噬细胞引发和LPS诱导的TNF产生增加以及随后的酒精性肝病（ALD）发展中的致病作用。由于增强的TNF表达在临床和实验性ALD的演变中起着重要作用，因此通过选择性PDE 4 B抑制剂下调其表达可能构成治疗ALD的新治疗方法。
Increased plasma and hepatic TNF-alpha 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-kappa B activation and TNF-alpha 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-alpha production by affecting NF-kappa 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-kappa B activation and transcriptional activity and subsequent priming of monocytes/macrophages leading to enhanced LPS-inducible TNF-alpha production. Selective inhibition of PDE4 by rolipram abrogated LPS-mediated TNF-alpha expression at both protein and mRNA levels in control and ethanol-treated cells. Notably, PDE4 inhibition did not affect LPS-inducible NF-kappa B activation but significantly decreased NF-kappa B transcriptional activity. These findings strongly support the pathogenic role of PDE4B in the ethanol-mediated priming of monocytes/macrophages and increased LPS-inducible 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.