IL-17 reduces TNF-induced Rantes and VCAM-1 expression.
Functional diversity of the memory T-cell-derived cytokine IL-17 was explored at the receptor level. IL-17 inhibited TNF-induced chemokine Rantes expression in human synovial fibroblasts and mouse lung fibroblasts. This inhibitory activity of IL-17 (IC50=0.2 ng/ml) was 6-fold more potent than its stimulatory activity on TNF-alpha-induced IL-6 secretion (ED50=1.2 ng/ml), measured in the same cells. IL-17 also inhibited the TNF-mediated expression of adhesion molecule VCAM-1, and the NF-kappaB binding to the VCAM-1 promoter-specific site, along with the inhibitor of NF-kappaB, IkappaB-beta. Neutralization of the human IL-17 receptor (IL-17R) by M202 antibody competitively reverses the IL-17-induced IL-6 upregulation. However, M202 only partially affected the inhibitions by IL-17. Yet, IL-17R was essential for the Rantes inhibition, as assessed in lung-derived fibroblasts from IL-17R gene deficient mice. Therefore, inhibitory and stimulatory functions of IL-17 involve receptor IL-17R but show distinct dose-responses and in turn different sensitivities to an IL-17R antagonizing antibody.
Biomedical Research Foundation (SBF), Lauchefeld 31, CH-9548 Matzingen, Switzerland. schnyder@cnrs-orleans.fr
Bruno
B
Schnyder
Silvia
S
Schnyder-Candrian
Andreas
A
Pansky
M Lienhard
ML
Schmitz
Markus
M
Heim
Bernhard
B
Ryffel
René
R
Moser
D000818:Animals; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism / Q000502:physiology*; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics; D053722:Receptors, Interleukin-17; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D018946:Chemokine CCL5; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1