In addition to down-regulation of LPS receptors, negative regulators of LPS signaling play an important role in LPS hyporesponsiveness (37). Negative regulators such as IRAK-M, SOCS-1, A20, and Tollip affect LPS signaling at different levels (37) and are important in LPS hyporesponsiveness and sensitization. Although IRAK-M and SOCS-1 directly inhibit LPS-induced IRAK-1 kinase activity, Tollip affects IL-1 receptor-associated IRAK-1 kinase and A20 directly inhibits IKK kinase and NFκB activation (37). Recent studies have shown that up-regulation of IRAK-M is essential for hyporesponsiveness to a second endotoxin stimulus in Kupffer cells (26). In this study, we show that acute exposure of human monocytes to alcohol for up to 1 day results in increased IRAK-M mRNA and protein levels. Previous studies from our laboratory have shown that acute in vivo and in vitro alcohol induces SOCS-1 expression to affect proinflammatory cytokine signaling (38). Increased IRAK-M levels were accompanied by decreased LPS-induced IRAK-1 (17) and IKK kinase activity and decreased NFκB binding along with IκBα degradation. Acute alcohol exposure not only decreased NFκB DNA binding but also reduced its transactivation potential. This is
