title: Stabilization of tumor necrosis factor-alpha mRNA in macrophages in response to chronic ethanol exposure.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is one of a number of cytokines implicated in the progression of alcohol-induced liver disease. Activation of hepatic macrophages by lipopolysaccharide (LPS) during exposure to ethanol is thought to be an important mechanism for stimulation of TNF-alpha expression. Chronic exposure of macrophages to ethanol, both in vivo after ad libitum feeding of ethanol for 4 weeks and in culture for 48 h, has an impact on specific elements within the LPS-stimulated signaling cascade, disrupting both transcriptional and posttranscriptional regulation of TNF-alpha biosynthesis. Stabilization of TNF-alpha mRNA after chronic exposure to ethanol is one important mechanism for increased TNF-alpha production by hepatic macrophages. Increased LPS stimulation of p38 mitogen-activated protein kinase contributes to this stabilization of TNF-alpha mRNA in macrophages. Stabilization of TNF-alpha mRNA after chronic exposure to ethanol requires both cis-acting elements in the TNF-alpha mRNA and trans-acting mRNA-binding proteins. The adenosine plus uridine-rich element in the 3' untranslated region of the TNF-alpha mRNA is an important regulator of TNF-alpha mRNA stability. Its activity is required for stabilization of TNF-alpha mRNA induced by chronic exposure to ethanol. Moreover, results from studies have demonstrated that at least one mRNA-binding protein, HuR, is also involved in stabilization of TNF-alpha mRNA stability after chronic exposure to ethanol. Taken together, the results from these studies identify the regulation of TNF-alpha mRNA stability as a novel mechanism by which chronic exposure to ethanol increases the expression of TNF-alpha.
authors.affiliation: Department of Nutrition, Case Western Reserve University, 2123 Abington Road, Room 201, Cleveland, OH 44106-4906, USA. len2@po.cwru.edu
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D000818:Animals; D000431:Ethanol / Q000008:administration & dosage*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol