Differentiation regulates interleukin-1β-induced cyclo-oxygenase-2 in human articular chondrocytes: role of p38 mitogen-activated protein kinase

Chondrocyte dedifferentiation has been noted in osteoarthritic cartilage, but the contribution of this phenomenon is poorly understood. Interleukin (IL)-1β, the major pro-inflammatory cytokine found in osteoarthritic synovial fluid, induces the dedifferentiation of cultured articular chondrocytes, w...

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Published in:Biochemical journal 2002-03, Vol.362 (2), p.367-373
Main Authors: THOMAS, Béatrice, THIRION, Sylvie, HUMBERT, Lydie, TAN, Lujian, GOLDRING, Mary B., BÉRÉZIAT, Gilbert, BERENBAUM, Francis
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container_title Biochemical journal
container_volume 362
creator THOMAS, Béatrice
THIRION, Sylvie
HUMBERT, Lydie
TAN, Lujian
GOLDRING, Mary B.
BÉRÉZIAT, Gilbert
BERENBAUM, Francis
description Chondrocyte dedifferentiation has been noted in osteoarthritic cartilage, but the contribution of this phenomenon is poorly understood. Interleukin (IL)-1β, the major pro-inflammatory cytokine found in osteoarthritic synovial fluid, induces the dedifferentiation of cultured articular chondrocytes, whereas E-series prostaglandins (PGE) are capable of inducing cell differentiation. Since PGE2 synthesis is up-regulated by IL-1β, we addressed the question of whether the state of chondrocyte differentiation may influence the production of IL-1-induced PGE2 by modulating cyclooxygenase (COX)-2 expression. Immortalized human articular chondrocytes, (tsT/AC62) cultured in monolayer after passage through alginate matrix (alg+) produced 5-fold greater amounts of PGE2 than continuous monolayer cultures (alg-) after stimulation with IL-1β. Moreover, IL-1β induced COX-2 expression at 0.01ng/ml in (alg+) cells, whereas a 100-fold higher dose of cytokine was necessary for stimulation in (alg-) cells. SB203580, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor, completely abolished the IL-1β-induced COX-2 mRNA. Overexpression of p38 MAPK induces a COX-2 reporter, whereas overexpression of dominant negative p38 MAPK represses IL-1β-induced promoter expression. Interestingly, IL-1β-induced p38 MAPK activity was greatly enhanced in (alg+) compared with (alg-) cells. Our results suggest that differentiated articular chondrocytes are highly responsive to IL-1β and that p38 MAPK mediates this response by inducing COX-2 gene expression.
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title Differentiation regulates interleukin-1β-induced cyclo-oxygenase-2 in human articular chondrocytes: role of p38 mitogen-activated protein kinase
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