INHIBITION OF THE KUPFFER CELL INFLAMMATORY RESPONSE BY ACUTE ETHANOL- NF-KAPPA-B ACTIVATION AND SUBSEQUENT CYTOKINE PRODUCTION

Suppression of host defense mechanisms plays a critical role in the re sponse to infectious agents in patients with alcohol-induced liver dis ease. Kupffer cells, the resident hepatic macrophage population, are a n essential component of host defense mechanisms against infection. Th us, regulation of the Kupffer cell inflammatory response by ethanol ma y be a key component of that immunosuppression. The aim of this study is to test the hypothesis that ethanol directly and specifically inhib its Kupffer cell activation. Kupffer cells were incubated in 100 mM et hanol for 90 minutes, whereupon cells were washed and incubated withou t ethanol for LPS activation. Such treatments lead to inhibition of LP S-mediated NF-kappa B activation. Consistent with these data, steady s tate levels of TNF-alpha and TNF-alpha secretion were depressed throug hout a range of LPS concentrations. The inhibition induced by ethanol was time dependent and completely reversible. These data show that the suppressive effects of ethanol affect the the earliest steps of the L PS signal transduction cascade as it is currently understood. (C) 1996 Academic Press. Inc.