Stabilization of tumor necrosis factor-alpha mRNA in macrophages in response to chronic ethanol exposure

Abstract 

Tumor necrosis factor-alpha (TNF-α) 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-α 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-α biosynthesis. Stabilization of TNF-α mRNA after chronic exposure to ethanol is one important mechanism for increased TNF-α production by hepatic macrophages. Increased LPS stimulation of p38 mitogen-activated protein kinase contributes to this stabilization of TNF-α mRNA in macrophages. Stabilization of TNF-α mRNA after chronic exposure to ethanol requires both cis-acting elements in the TNF-α mRNA and trans-acting mRNA-binding proteins. The adenosine plus uridine–rich element in the 3′ untranslated region of the TNF-α mRNA is an important regulator of TNF-α mRNA stability. Its activity is required for stabilization of TNF-α 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-α mRNA stability after chronic exposure to ethanol. Taken together, the results from these studies identify the regulation of TNF-α mRNA stability as a novel mechanism by which chronic exposure to ethanol increases the expression of TNF-α.

Keywords: Kupffer cells, Lipopolysaccharide, HuR, 3′ untranslated regions, mRNA stability