IL-6 induces NF-kappa B activation in the intestinal epithelia.
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-kappaB, 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-kappaB pathway. Basolateral IL-6 stimulation results in a maximal induction of NF-kappaB activation and NF-kappaB 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-kappaB. 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-kappaB activation and ICAM-1 expression. In summary, we demonstrate the activation of NF-kappaB by IL-6 in intestinal epithelia and the down-regulation of NF-kappaB 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.
Wang
Lixin
L
Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA 30322, USA.
Walia
Baljit
B
Evans
John
J
Gewirtz
Andrew T
AT
Merlin
Didier
D
Sitaraman
Shanthi V
SV
D018938:Caco-2 Cells; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011506:Proteins / Q000502:physiology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D012097:Repressor Proteins; D020218:Response Elements / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000276:immunology*; D000093242:Interleukin-6 Inhibitors
D004268:DNA-Binding Proteins; D018799:Intercellular Adhesion Molecule-1; D015850:Interleukin-6; D016328:NF-kappa B; D011506:Proteins; D019947:Receptors, Interleukin-6; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors; C106644:SOCS3 protein, human