alcohol on the LPS-induced signaling pathway (Fig. 8). Acute alcohol exposure of monocytes appears to induce hyporesponsiveness to LPS by increasing IRAK-M levels. However, chronic alcohol exposure decreases IRAK-M levels resulting in sensitization to subsequent LPS stimulation. IRAK-M thus serves as a molecular switch to convert an acute alcohol-induced anti-inflammatory phenotype to chronic alcohol-induced hyperinflammatory phenotype. Our results revealed that mechanisms involved in acute alcohol-induced LPS hyporesponsiveness involve decreased IRAK-1 and IKK kinase activity, decreased MAPK-ERK activation, and reduced NFκB activation independent of IκBα degradation. In contrast, reduced IRAK-M after chronic alcohol exposure of monocytes was associated with increased IRAK-1 and IKK kinase activity, increased MAPK-ERK activity, and IκBα-dependent NFκB activity (Fig. 7). These effects of acute or chronic alcohol exposure were found to be independent of CD14 and TLR4 surface expression, indicating that alcohol exclusively alters intracellular signaling molecules to exert its effect on proinflammatory cytokine expression.
