IL-1beta induction of NF-kappaB activation in human intestinal epithelial cells is independent of oxyradical signaling.
IL-1beta stimulation of cultured epithelial cells induces the degradation of IkappaBalpha and the consequent nuclear translocation of NF-lambdaB, a critical proinflammatory transcription factor in the mucosal host immune response. The role of reactive oxygen intermediates, serine protease activity, and tyrosine kinase activity in the activation of NF-kappaB is weakly conserved across various cell lineages and has not been defined in human enterocytes, a major target of oxidant stress in sepsis, thermal injury, and hemorrhagic shock. We report here that in Caco-2BBe cells, a transformed human colon cancer cell line with features of small intestinal epithelial cells in culture, exposure to oxidant stress (hydrogen peroxide 1-10 mM) did not induce NF-kappaB activation. Similarly, scavenging of free radicals and oxidants by pyrrolidine dithiocarbamate and dimethyl sulfoxide did not block IL-1beta-induced IkappaBalpha degradation and NF-kappaB activation. Genistein, a nonspecific tyrosine kinase inhibitor, also had no effect on IL-1beta-mediated effects on NF-kappaB. Serine protease inhibition by tosyl-lysine-chloromethylketone and tosyl-phenylalanine-chloromethylketone inhibited IkappaBalpha degradation and NF-kappaB activation stimulated by IL-1beta. Our data highlight the strong divergence between epithelial and mononuclear cells in the signal transduction pathways relating IL-1beta stimulation and NF-kappaB nuclear translocation.
Parikh
A A
AA
Department of Surgery, University of Cincinnati Medical Center, and the Shriners Hospital for Children, Ohio 45229, USA.
Moon
M R
MR
Pritts
T A
TA
Fischer
J E
JE
Szabó
C
C
Hasselgren
P O
PO
Salzman
A L
AL
D000230:Adenocarcinoma; D000975:Antioxidants / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003110:Colonic Neoplasms; D004268:DNA-Binding Proteins / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D016877:Oxidants; D011759:Pyrrolidines; D011994:Recombinant Proteins; D013859:Thiocarbamates; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid; D006861:Hydrogen Peroxide; D004121:Dimethyl Sulfoxide