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 hypothesis that interleukin-1 receptor-associated kinase (IRAK), a downstream signaling molecule of toll-like receptors, regulates the response to LPS in Kupffer cells after ethanol treatment was evaluated. C57BL/6 mice were given ethanol intragastrically, and LPS was injected 1 or 21 h later. One hour after ethanol treatment, serum transaminases after LPS were 60% of control, while ethanol increased these parameters about 3-fold 21 h after ethanol. Pretreatment with antibiotics blocked these effects of ethanol. In Kupffer cells from mice treated with ethanol 1 h earlier, LPS-induced TNFalpha production, and IRAK expression and activity and NFkappaB were decreased 50-60% of control. In contrast, in Kupffer cells from mice treated with ethanol 21 h earlier, LPS-induced TNFalpha production, expression and activity of IRAK were increased 1.5-fold over controls, while NFkappaB was elevated 3-fold. These data indicate that ethanol-induced tolerance and sensitization of Kupffer cells to endotoxin in mice involve IRAK.
Yamashina
S
S
Laboratory of Hepatobiology and Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7365, USA.
Wheeler
M D
MD
Rusyn
I
I
Ikejima
K
K
Sato
N
N
Thurman
R G
RG
D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D066298:In Vitro Techniques; D053592:Interleukin-1 Receptor-Associated Kinases; D007728:Kupffer Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D011494:Protein Kinases / Q000378:metabolism*; D000637:Transaminases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D000637:Transaminases; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases