Differentiation regulates interleukin-1beta-induced cyclo-oxygenase-2 in human articular chondrocytes: role of p38 mitogen-activated protein kinase. Academic Article uri icon

Overview

abstract

  • Chondrocyte dedifferentiation has been noted in osteoarthritic cartilage, but the contribution of this phenomenon is poorly understood. Interleukin (IL)-1beta, 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 PGE(2) synthesis is up-regulated by IL-1beta, we addressed the question of whether the state of chondrocyte differentiation may influence the production of IL-1-induced PGE(2) 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 PGE(2) than continuous monolayer cultures (alg-) after stimulation with IL-1beta. Moreover, IL-1beta induced COX-2 expression at 0.01 ng/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-1beta-induced COX-2 mRNA. Overexpression of p38 MAPK induces a COX-2 reporter, whereas overexpression of dominant negative p38 MAPK represses IL-1beta-induced promoter expression. Interestingly, IL-1beta-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-1beta and that p38 MAPK mediates this response by inducing COX-2 gene expression.

publication date

  • March 1, 2002

Research

keywords

  • Cartilage, Articular
  • Chondrocytes
  • Gene Expression Regulation, Enzymologic
  • Interleukin-1
  • Isoenzymes
  • Mitogen-Activated Protein Kinases
  • Prostaglandin-Endoperoxide Synthases

Identity

PubMed Central ID

  • PMC1222396

Scopus Document Identifier

  • 0036499910

Digital Object Identifier (DOI)

  • 10.1042/0264-6021:3620367

PubMed ID

  • 11853544

Additional Document Info

volume

  • 362

issue

  • Pt 2