In contrast to acute alcohol, chronic alcohol exposure of human monocytes induced sensitization to LPS resulting in increased TNF-α expression. Exposure of monocytes to alcohol from 4 to 7 days shows a gradual increase in NFκB activation as well as TNF-α production. These results are consistent with the hypothesis that prolonged alcohol sensitizes to LPS as has been proposed in alcoholic liver disease wherein alcohol-induced increase in gut-derived endotoxin results in increased proinflammatory cytokine induction (43). Several studies have shown that Kupffer cells treated with chronic alcohol in vitro or in vivo were highly sensitive to LPS and showed increased TNF-α production (44). Chronic alcohol-induced sensitization in Kupffer cells to LPS has been attributed to increased IRAK kinase expression and activity and in part due to increased CD14 expression (33). Our studies demonstrated that chronic alcohol exposure of human monocytes decreases IRAK-M expression and increases IRAK-1 kinase activity without changes in CD14 and TLR4 expression. This is consistent with studies where monocytes from patients with advanced cirrhosis showed that up-regulation of TNF-α production was due to increased IRAK kinase, increased
