Tolerance and sensitization to endotoxin in Kupffer cells caused by acute ethanol involve interleukin-1 receptor-associated kinase

Ethanol changes sensitivity of Kupffer cells to endotoxin. Here, the hypoth esis that interleukin-l receptor-associated kinase (IRAK), a downstream sig naling molecule of toll-like receptors, regulates the response to LPS in Ku pffer cells after ethanol treatment was evaluated. C57BL/6 mice were given ethanol intragastrically, and LPS was injected 1 or 21 h later. One hour af ter ethanol treatment, serum transaminases after LPS were 60% of control, w hile ethanol increased these parameters about 3-fold 21 h after ethanol. Pr etreatment with antibiotics blocked these effects of ethanol. In Kupffer ce lls from mice treated with ethanol 1 h earlier, LPS-induced TNF alpha produ ction, and IRAK expression and activity and NF kappaB were decreased 50-60% of control. In contrast, in Kupffer cells from mice treated with ethanol 2 1 h earlier, LPS-induced TNF alpha production, expression and activity of I RAK were increased 1.5-fold over controls, while NF kappaB was elevated S-f old. These data indicate that ethanol-induced tolerance and sensitization o f Kupffer cells to endotoxin in mice involve IRAK. (C) 2000 Academic Press.