Oxidative products from alcohol metabolism differentially modulate pro-inflammatory cytokine expression in Kupffer cells and hepatocytes. (September 2016)

• Record Type: Journal Article
• Authors: Dong, Daoyin; Zhong, Wei; Sun, Qian; Zhang, Wenliang; Sun, Xinguo; Zhou, Zhanxiang
• Is Part Of: Cytokine. Volume 85(2016)
• Page Start: 109
• Page End: 119
• Publication Date: 2016-09
• Subjects: Alcohol -- Kupffer cells -- Hepatocytes -- 4-HNE -- Cytokines -- Chemokines; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2016.06.014
• Languages: English
• ISSNs: 1043-4666

Abstract

Highlights: Kupffer cells and hepatocytes produce different cytokines/chemokines in ALD. 4-HNE inhibits LPS-induced cytokine production in Kupffer cells. 4-HNE exaggerates TNF-α-induced cytokine production in hepatocytes. The diverse effect of 4-HNE involves differentially modulated mRNA stability. Abstract: Pro-inflammatory cytokines play a vital role in the pathogenesis of alcoholic steatohepatitis. The present study was to determine the role of alcohol-induced oxidative stress in modulating cytokine production. A rat model of alcohol consumption was used to determine alcohol-induced hepatic cytokine expression. Chronic alcohol exposure caused lipid accumulation, oxidative stress, and inflammation in the livers of Wistar rats. The role of oxidative stress in regulating cell type-specific cytokine production was further dissected in vitro . Lipopolysaccharide (LPS) dose-dependently upregulated TNF-α, MIP-1α, MCP-1, and CINC-1 in Kupffer cells-SV40, whereas TNF-α dose-dependently induced CINC-1, IP-10, and MIP-2 expression in H4IIEC3 hepatoma cells. An additive effect on cytokine production was observed in both Kupffer cells-SV40 and hepatocytes when combined hydrogen peroxide with LPS or TNF-α, respectively, which was associated with NF-κB activation and histone H3 hyper-acetylation. Unexpectedly, an inhibitory effect of 4-hydroxynonenal on cytokine production was revealed in LPS-treated Kupffer cells-SV40. Mechanistic study showed that 4-hydroxynonenal significantly enhanced mRNA degradation of TNF-α, MCP-1, and MIP-1α, and decreased the protein levels of MCP-1 in LPS-stimulated Kupffer cells-SV40 through reducing the phosphorylation of mRNA binding proteins. This study suggests that Kupffer cells and hepatocytes express distinct pro-inflammatory cytokines/chemokines in response to alcohol intoxication, and oxidative products (4-hydroxynonenal) differentially modulate pro-inflammatory cytokine/chemokine production via NF-κB signaling, histone acetylation, and mRNA stability.