Selective activation of the mitogen-activated protein kinase subgroups c-Jun NH2 terminal kinase and p38 by IL-1 and TNF in human articular chondrocytes.

Abstract

Previous studies suggested that tyrosine kinase activation is an important signal transduction event in the IL-1 response of chondrocytes. The present study identifies the mitogenactivated protein (MAP) kinases extracellular signal-regulated kinase (ERK)-1 and ERK-2 as major tyrosine phosphorylated proteins in IL-1 stimulated chondrocytes. Kinase assays on immunoprecipitates with myelin basic protein as substrate showed 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 2 terminal kinase (JNK)-1, JNK-2, and p38 proteins. These kinases were time-dependently activated by IL-1. Among other chondrocyte activators tested, only TNF activated all three of the MAP kinase subgroups. JNK and p38 were not activated by any of the other cytokines and growth factors tested. However, ERK was also activated by PDGF, IGF-1, and IL-6. Phorbol 12-myristate 13-acetate, calcium ionophore, and cAMP analogues only increased ERK activity but had no significant 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 second messenger agonists. In contrast, JNK and p38 are only activated by IL-1 or TNF, suggesting that these kinases participate in the induction of the catabolic program in cartilage. ( J. Clin. Invest. 1996. 98:2425-2430.)

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

“…The MAPK pathway consists of ERK, p38, and JNK. These MAPK subtypes are constitutively expressed in articular chondrocytes and transiently activated by numerous stimuli, including IL-1␤ and tumor necrosis factor ␣ (TNF␣) (13). Several studies suggest that MAPKs are also able to modulate the IL-1␤-induced NF-B pathway (14).…”

Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction

“…Among these molecules, p38 MAPK is considered to be one of the most important signals for TNF-mediated inflammatory responses. This supposition is based on 4 important observations: 1) p38 MAPK is strongly activated in RA synovial membrane but not in the synovial membrane of patients with degenerative joint disease (9); 2) active p38 MAPK is predominantly expressed in endothelial and lining layer cells, which represent 2 regions of significant importance when considering the necessity of transendothelial migration by blood-derived cells in the course of inflammation as well as the role of the lining layer in the formation of the destructive pannus (10); 3) synthetic blockers of p38 MAPK have potent antiinflammatory properties and inhibit experimental arthritis in rodents (11); and 4) p38 MAPK is involved in regulating the expression of many proinflammatory cytokines, including TNF (12). Thus, p38 MAPK is pivotally involved in TNF expression induced by lipopolysaccharide or IL-1 and is, therefore, thought to play a major role in inducing TNF expression during inflammatory disease in humans (13).…”

Interleukin-1β stimulates matrix metalloproteinase-2 expression via a prostaglandin E2-dependent mechanism in human chondrocytes

“…On binding to its receptor, IL-1β transduces signals that regulate gene expression (Geng et al, 1996). These signaling pathways include the mitogen activated protein kinase (MAPK) family, including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase and p38.…”

“…These signaling pathways include the mitogen activated protein kinase (MAPK) family, including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase and p38. However, the detailed of the actions of MAPKs as initiated by IL-1β on chondrocytes regulation are unclear, but it is known that both ERK-dependent and p38-dependent processes are implicated (Geng et al, 1996;Lo et al, 1998).…”