SELECTIVE ACTIVATION OF THE MITOGEN-ACTIVATED PROTEIN-KINASE SUBGROUPS C-JUN NH2 TERMINAL KINASE AND P38 BY IL-1 AND TNF IN HUMAN ARTICULARCHONDROCYTES

Previous studies suggested that tyrosine kinase activation is an impor tant signal transduction event in the IL-1 response of chondrocytes. T he present study identifies the mitogen-activated protein (MAP) kinase s extracellular signal-regulated kinase (ERK)-1 and ERK-2 as major tyr osine phosphorylated proteins in IL-1 stimulated chondrocytes, Kinase assays on immunoprecipitates with myelin basic protein as substrate sh owed that ERK-1 and ERK-2 activation was detectable within 5 min after IL-1 stimulation and decreased to baseline within 60 min, Analysis of other members of the MAP kinase family showed that chondrocytes also express c-Jun NH, terminal kinase (JNK)-1, JNK-2, and p38 proteins. Th ese kinases were time-dependently activated by IL-1, Among other chond rocyte activators tested, only TNF activated all three of the MAP kina se subgroups, JNK and p38 were not activated by any of the other cytok ines and growth factors tested, However, ERK was also activated by PDG F, IGF-1, and IL-6. Phorbol 12-myristate 13-acetate, calcium ionophore , and cAMP analogues only increased ERK activity but had no significan t effects on JNK or p38. These results suggest differential activation of MAP kinase subgroups by extracellular stimuli. ERK is activated in response to qualitatively diverse extracellular stimuli and various s econd messenger agonists, In contrast, JNK and p38 are only activated by IL-1 or TNF, suggesting that these kinases participate in the induc tion of the catabolic program in cartilage.