title: Acute alcohol inhibits the induction of nuclear regulatory factor kappa B activation through CD14/toll-like receptor 4, interleukin-1, and tumor necrosis factor receptors: a common mechanism independent of inhibitory kappa B alpha degradation?
abstract: BACKGROUND
  Nuclear translocation and DNA binding of the nuclear factor kappaB (NF-kappaB) is an early event in inflammatory cell activation in response to stimulation with bacterial components or cytokines. Cell activation via different receptors culminates in a common pathway leading to NF-kappaB activation and proinflammatory cytokine induction. We have previously shown that acute alcohol inhibits NF-kappaB activation by lipopolysaccharide (LPS) in human monocytes. Here we investigated whether acute alcohol treatment of human monocytes also inhibits NF-kappaB when induced through activation of the interleukin (IL)-1 or tumor necrosis factor (TNF) receptors.
  
  
  METHODS
  Human peripheral blood monocytes were treated with LPS, TNFalpha, and IL-1beta in the presence or absence of 25mM alcohol for 1 hr. NF-kappaB activation was determined by electrophoretic mobility shift assays using nuclear extracts. Inhibitory kappaB(alpha) (IkappaB(alpha)) was estimated by Western blotting in cytoplasmic extracts. Chinese hamster ovary cells expressing human CD14 were treated with LPS in the presence or absence of alcohol to study NF-kappaB and IkappaB(alpha) regulation.
  
  
  RESULTS
  Our results indicate that acute alcohol inhibits IL-1beta- and TNFalpha-induced NF-kappaB activation. We further show in CD14/toll-like receptor 4-expressing Chinese hamster ovary cells the specificity of alcohol-mediated inhibition of NF-kappaB via the toll-like receptor 4/CD14 receptors. Inhibition of NF-kappaB by acute alcohol was concomitant with decreased levels of the IkappaB(alpha) molecule in the cytoplasm of LPS, IL-1, and TNFalpha-activated monocytes.
  
  
  CONCLUSIONS
  These data suggest a unique, IkappaB(alpha)-independent pathway for the inhibition of NF-kappaB activation by acute alcohol in monocytes. Universal inhibition of NF-kappaB by acute alcohol via these various receptor systems suggests a target for the effects of alcohol in the NF-kappaB activation cascade that is downstream from IkappaB(alpha) degradation. Further, these results demonstrate that acute alcohol is a potent inhibitor of NF-kappaB activation by mediators of early (LPS) or late (IL-1, TNF(alpha)) stages of inflammation in monocytes.
authors.affiliation: University of Massachusetts Medical School, Department of Medicine, Worcester 01605-2324, USA.
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Angela
authors.initials: A
authors.lastname: Dolganiuc
authors.forename: Gary
authors.initials: G
authors.lastname: Bellerose
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Laszlo
authors.initials: L
authors.lastname: Romics
authors.forename: Rabia
authors.initials: R
authors.lastname: Nizamani
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D029721:Drosophila Proteins; D000431:Ethanol / Q000008:administration & dosage*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism* / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D029721:Drosophila Proteins; D020672:I-kappa B Proteins; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha; D000431:Ethanol