INTERLEUKIN-17-INDUCED GENE-EXPRESSION IN ARTICULAR CHONDROCYTES IS ASSOCIATED WITH ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES AND NF-KAPPA-B

This study examines intracellular signaling events associated with the activation of chondrocytes by the cytokine interleukin-17 (IL-17). St imulation of normal human articular chondrocytes with IL-17 induced ni tric oxide (NO) production, concomitant with an increase in transcript s and de novo translation products of the inducible nitric oxide synth ase (iNOS) and cyclooxygenase-a (COX-2) genes. Several other genes ass ociated with inflammation and cartilage degradation, such as IL-1 beta , IL-6, and stromelysin, were also up-regulated in IL-17-treated chond rocytes. Among signaling events displaying early response to IL-17 in chondrocytes were the mitogen-activated protein (MAP) kinases ERK1, ER K2, JNK, and p38. DNA binding activity of NF-kappa B was also signific antly induced. IL-17 effects on NO release, as well, as iNOS, COX-2, a nd IL-6 protein expression, were inhibited by the anti-inflammatory dr ug dexamethasone, Importantly, dexamethasone blunted IL-17-dependent a ctivation of MAP kinases, suggesting a mechanistic relationship betwee n these activities and the aforementioned gene expression responses. S imilar effects of a lesser extent were observed with the p38-specific inhibitor SB203580, These results suggest that IL-17 activation of cho ndrocytes is associated with and depends at least in part on the activ ation of MAP kinases and NF-kappa B.