Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB.
This study examines intracellular signaling events associated with the activation of chondrocytes by the cytokine interleukin-17 (IL-17). Stimulation of normal human articular chondrocytes with IL-17 induced nitric oxide (NO) production, concomitant with an increase in transcripts and de novo translation products of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes. Several other genes associated with inflammation and cartilage degradation, such as IL-1beta, IL-6, and stromelysin, were also up-regulated in IL-17-treated chondrocytes. Among signaling events displaying early response to IL-17 in chondrocytes were the mitogen-activated protein (MAP) kinases ERK1, ERK2, JNK, and p38. DNA binding activity of NF-kappaB was also significantly induced. IL-17 effects on NO release, as well as iNOS, COX-2, and IL-6 protein expression, were inhibited by the anti-inflammatory drug dexamethasone. Importantly, dexamethasone blunted IL-17-dependent activation of MAP kinases, suggesting a mechanistic relationship between these activities and the aforementioned gene expression responses. Similar effects of a lesser extent were observed with the p38-specific inhibitor SB203580. These results suggest that IL-17 activation of chondrocytes is associated with and depends at least in part on the activation of MAP kinases and NF-kappaB.
Division of Arthritis Research, The Scripps Research Institute, La Jolla, California 92037, USA.
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T
Shalom-Barak
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Quach
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M
Lotz
D001168:Arthritis / Q000209:etiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D020381:Interleukin-17; D016328:NF-kappa B; D009569:Nitric Oxide; D003907:Dexamethasone; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases