title: ERK1/2 and Egr-1 contribute to increased TNF-alpha production in rat Kupffer cells after chronic ethanol feeding.
abstract: Activation of Kupffer cells by lipopolysaccharide (LPS) is a critical step in the pathogenesis of alcoholic liver disease. Kupffer cells isolated from rats fed ethanol in their diet for 4 wk accumulated 4.3-fold more tumor necrosis factor (TNF)-alpha in response to LPS compared with pair-fed rats. In contrast, LPS-stimulated interleukin (IL)-1 accumulation was 50% lower after ethanol feeding. LPS-stimulated TNF-alpha mRNA accumulation was twofold higher after ethanol feeding, whereas IL-1beta mRNA accumulation was blunted. To understand the mechanisms for this differential response, we investigated the effects of ethanol on LPS-dependent signal transduction. Chronic ethanol feeding increased LPS-stimulated extracellular receptor-activated kinases 1/2 (ERK1/2) activation. Activation of ERK1/2 was required for maximal increases in TNF-alpha and IL-1beta mRNA and was associated with increased binding of early growth response-1 (Egr-1) to the TNF-alpha promoter after ethanol feeding. In contrast, ethanol feeding completely abrogated activation of nuclear factor-kappaB DNA-binding activity by LPS and had no effect on AP-1 binding. Together, these data suggest that enhanced activation of ERK1/2 and Egr-1 contributes to increased TNF-alpha production after chronic ethanol feeding.
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106-4906, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Jeanette R
authors.initials: JR
authors.lastname: Hill
authors.forename: Megan R
authors.initials: MR
authors.lastname: McMullen
authors.forename: Julia
authors.initials: J
authors.lastname: Frenkel
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D000437:Alcoholism / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D000431:Ethanol / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D017874:Immediate-Early Proteins; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases