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 response to infectious agents in patients with alcohol-induced liver disease. Kupffer cells, the resident hepatic macrophage population, are an essential component of host defense mechanisms against infection. Thus, regulation of the Kupffer cell inflammatory response by ethanol may be a key component of that immunosuppression. The aim of this study is to test the hypothesis that ethanol directly and specifically inhibits Kupffer cell activation. Kupffer cells were incubated in 100 mM ethanol for 90 minutes, whereupon cells were washed and incubated without ethanol for LPS activation. Such treatments lead to inhibition of LPS-mediated NF-kappa B activation. Consistent with these data, steady state levels of TNF-alpha and TNF-alpha secretion were depressed throughout 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 LPS signal transduction cascade as it is currently understood.
Fox
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Department of Pediatrics, Saint Louis University School of Medicine, Missouri 63110, USA. FOXES@SLUVCA.SLU.EDU
Cantrell
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Leingang
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D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation; D007700:Kinetics; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol