IRAK-1 kinase activity is regulated by a negative regulator of LPS signaling, IRAK-M, expressed in monocytes and demonstrated to play a critical role in hyporesponsiveness and sensitization to LPS (24 –26). IRAK-M acts by inhibiting dissociation of MyD88 and IRAK-1 to turn off down-stream signaling (24). Thus, we hypothesized that acute and chronic alcohol differently regulates IRAK-M in human monocytes to influence IRAK-1 kinase activity. Fig. 2C shows that IRAK-M mRNA was induced after LPS stimulation for 6 h in human monocytes. Although LPS-induced IRAK-M mRNA was increased by acute alcohol, chronic alcohol significantly decreased IRAK-M mRNA at baseline and in response to LPS stimulation (Fig. 2C). IRAK-M protein expression followed a similar pattern wherein acute alcohol increased and chronic alcohol exposure decreased IRAK-M levels in the cytoplasm of human monocytes (Fig. 2D). Thus, it is likely that acute alcohol exposure up-regulates IRAK-M and thereby inhibits IRAK-1 kinase activity whereas chronic alcohol-mediated down-regulation of IRAK-M could permit persistent activation of IRAK-1 kinase.
