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Synovial tissues of patients with rheumatoid arthritis (RA) have increased expression of COX-2. COX-2 expression in most tissues is highly regulated with rapid induction in response to inflammatory stimuli. Anti-inflammatory mediators, particularly glucocorticoids, inhibit up-regulation of COX-2 expression. Increased COX-2 expression in synovial tissues is driven by the pro-inflammatory cytokines IL-1 and TNF-α . These cytokines stimulate COX-2 transcription by activating transcription factors including NF-κ B and c/EBP. IL-1 also increases mRNA stability. Modulating influences by other cytokines and growth factors utilize the STAT family of transcription factors. In addition to cytokine networks, signalling via cell surface integrins can increase expression of COX-2. The intracellular pathways triggered by stimulation of integrins include phosphorylation of the ERK kinases.
PGE2, the major PG product of COX-2 in synoviocytes, has been shown to alter matrix metalloproteinase balance and to increase expression of the angiogenic factor, VEGF. In some cell types, constitutive over-expression of COX-2 is associated with phenotypic changes including increased resistance to apoptosis and production of angiogenic factors. To analyze the effect of COX-2 on synovial fibroblast-like cells, we have developed a method for highly efficient constitutive over-expression of COX-2 using a retroviral vector system. Early-passage synoviocytes stably transduced to express high levels of COX-2 can be evaluated for phenotypic changes that contribute to the pathogenesis of rheumatoid arthritis.
References
- Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol. 1997;1:15–19. [PubMed] [Google Scholar]
- Crofford LJ, Wilder RL, Ristimaki AP, Remmers EF, Epps HR, Hla T. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues: effects of interleukin-1β, phorbol ester, and corticosteroids. J Clin Invest. 1994;1:1095–1101. doi: 10.1172/JCI117060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crofford LJ, Tan B, McCarthy CJ, Hla T. NF-κ B is involved in the regulation of cyclooxygenase-2 expression by interleukin-1β in rheumatoid synoviocytes. . Arthritis Rheum. 1997;1:226–236. doi: 10.1002/art.1780400207. [DOI] [PubMed] [Google Scholar]
- Ben-Av P, Crofford LJ, Wilder RL, Hla T. Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. FEBS Lett. 1995;1:83–87. doi: 10.1016/0014-5793(95)00956-A. [DOI] [PubMed] [Google Scholar]
- Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995;1:493–501. doi: 10.1016/0092-8674(95)90127-2. [DOI] [PubMed] [Google Scholar]
- Ristimaki A, Garfinkel S, Wessendorf J, Maciag T, Hla T. Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation. J Biol Chem. 1994;1:11769–11775. [PubMed] [Google Scholar]