Interleukin-17 is a potent immuno-modulator and regulator of normal human intestinal epithelial cell growth.
Upregulation of the T-cell derived cytokine interleukin (IL-17) was reported in the inflamed intestinal mucosa of patients with inflammatory bowel disorders. In this study, we analyzed the effect of IL-17 on human intestinal epithelial cell (HIEC) turnover and functions. Proliferation and apoptosis in response to IL-17 was monitored in HIEC (cell counts, [(3)H]thymidine incorporation method, and annexinV-PI-apoptosis assay). Signalling pathways were analyzed by Western blots, electromobility shift assay, and immunofluorescence studies. IL-17 proved to be a potent inhibitor of HIEC proliferation without any pro-apoptotic/necrotic effect. The growth inhibitory effect of IL-17 was mediated via the p38 stress kinase. Consequently, the p38-SAPkinase-inhibitor SB203580 abrogated this anti-mitotic effect. In parallel, IL-17 provoked the degradation of IkappaBalpha, allowing nuclear translocation of the p65 NF-kappaB subunit and induction of the NF-kappaB-controlled genes IL-6 and -8. IL-17 potently blocks epithelial cell turnover while at the same time amplifying an inflammatory response in a positive feedback manner.
Schwartz
S
S
Children's Hospital, Mucosal Immunology Laboratory, University of Bonn, Germany.
Beaulieu
J F
JF
Ruemmele
F M
FM
D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D020381:Interleukin-17; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases