Although the role of MAPK regulation in LPS hyporesponsiveness of monocytes and macrophages have been established (38, 39), there are no studies indicating a role for ERK, JNK, and p38 MAPK in increased sensitization to LPS. In this study, we show that prior chronic alcohol exposure for 7 days selectively increases subsequent LPS-induced ERK MAPK activation that contributes to the increased LPS-induced TNF-α production after chronic alcohol treatment. This was suggested by the observation that a specific ERK kinase inhibitor could prevent the chronic alcohol-induced increase in TNF-α production. Similar to chronic alcohol-exposed Kupffer cells (49), these studies indicate an important role for ERK MAPK kinases in addition to increased NFκB activity in chronic alcohol exposed human monocytes. We also found that chronic alcohol exposure does not affect p38 and JNK MAPK. It appears that reduced IRAK-M plays a pivotal role in down-stream activation of IRAK-1 kinase and subsequent activation of IKK and ERK-MAPK in chronic alcohol induced TNF-α production in human monocytes. The precise mechanisms of IRAK-M reduction by chronic alcohol exposure of human monocytes will be explored in future studies.
