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The Journal of Immunology, 2003, 171: 3194-3201.
Copyright © 2003 by The American Association of Immunologists

IL-6 Induces NF-{kappa}B Activation in the Intestinal Epithelia 1

Lixin Wang*, Baljit Walia*, John Evans2,*, Andrew T. Gewirtz{dagger}, Didier Merlin* and Shanthi V. Sitaraman3,*

* Department of Medicine, Division of Digestive Diseases and {dagger} Department of Pathology, Epithelial Pathobiology Unit, Emory University, Atlanta, GA 30322

IL-6 is a potent proinflammatory cytokine that has been shown to play an important role in the pathogenesis of inflammatory bowel disease (IBD). It is classically known to activate gene expression via the STAT-3 pathway. Given the crucial role of IL-6 in the pathogenesis of chronic intestinal inflammation, it is not known whether IL-6 activates NF-{kappa}B, a central mediator of intestinal inflammation. The model intestinal epithelial cell line, Caco2-BBE, was used to study IL-6 signaling and to analyze whether suppressor of cytokine signaling 3 (SOCS-3) proteins play a role in the negative regulation of IL-6 signaling. We show that IL-6 receptors are present in intestinal epithelia in a polarized fashion. Basolateral IL-6 and, to a lesser extent, apical IL-6 induces the activation of the NF-{kappa}B pathway. Basolateral IL-6 stimulation results in a maximal induction of NF-{kappa}B activation and NF-{kappa}B nuclear translocation at 2 h. IL-6 induces polarized expression of ICAM-1, an adhesion molecule shown to be important in the neutrophil-epithelial interactions in IBD. Using various deletion constructs of ICAM-1 promoter, we show that ICAM-1 induction by IL-6 requires the activation of NF-{kappa}B. We also demonstrate that overexpression of SOCS-3, a protein known to inhibit STAT activation in response to IL-6, down-regulates IL-6-induced NF-{kappa}B activation and ICAM-1 expression. In summary, we demonstrate the activation of NF-{kappa}B by IL-6 in intestinal epithelia and the down-regulation of NF-{kappa}B induction by SOCS-3. These data may have mechanistic and therapeutic implications in diseases such as IBD and rheumatoid arthritis in which IL-6 plays an important role in the pathogenesis.




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