IL-1β stimulation of cultured epithelial cells induces the degradation of IκBα and the consequent nuclear translocation of NF-λB, 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-κB 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-κB activation. Similarly, scavenging of free radicals and oxidants by pyrrolidine dithiocarbamate and dimethyl sulfoxide did not block IL-1β-induced IκBα degradation and NF-κB activation. Genistein, a nonspecific tyrosine kinase inhibitor, also had no effect on IL-1β-mediated effects on NF-κB. Serine protease inhibition by tosyl-lysine-chloromethylketone and tosyl-phenylalanine-chloromethylketone inhibited IκBα degradation and NF-κB activation stimulated by IL-1β. Our data highlight the strong divergence between epithelial and mononuclear cells in the signal transduction pathways relating IL-1β stimulation and NF-κB nuclear translocation.
*Department of Surgery, University of Cincinnati Medical Center, and the Shriners Hospital for Children, Cincinnati, Ohio 45229
†Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio 45229
Received 21 May 1998; first review completed 4 Mar 1999; accepted in final form 6 Jul 1999
Address reprint requests to Per-Olof Hasselgren, MD, Department of Surgery, University of Cincinnati, 231 Bethesda Avenue, Mail Location 558, Cincinnati, Ohio 45267-0558.
Supported in part by grant 9650090N from the American Heart Association, grant 1R01HL59352-01 from National Institutes of Health, and grant 8510 from the Shriners of North America.
©2000The Shock Society