Studies on acute alcohol-induced immunosuppression leading to increased susceptibility to infections and chronic alcohol-mediated liver disease have indicated a key role for innate immune cells. In vivo studies in mouse models have shown that while chronic alcohol increases sensitivity of macrophages to LPS (7), acute alcohol in human peripheral blood monocytes decreases LPS-mediated proinflammatory cytokines (14). The precise intracellular signaling molecules involved in reversing the acute immunosuppressive effects of alcohol to a hyperinflammatory state are not well understood. In this study, for the first time using human peripheral blood monocytes, we demonstrate the signaling molecules involved in acute alcohol-induced hyporesponsiveness to LPS and chronic alcohol-mediated sensitivity of monocytes to subsequent LPS stimulation. Our results show that the primary target of alcohol is IRAK-M, a negative modulator of LPS signaling, that is involved in the opposite effects of acute and chronic 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
