Effects of hypoxia on the expression and activity of cyclooxygenase 2 in fibroblast-like synoviocytes - Interactions with monocyte-derived soluble mediators

Objective: Rheumatoid synovium is characterized by hyperplasia of fibroblast-like (type B) synoviocytes (FLS), infiltration with mononuclear leukocytes, and tissue hypoxia. Although the latter is well documented, it has received little attention in dissection of the biochemical events that mediate the inflammatory lesion in rheumatoid arthritis (RA). Therefore, this study was designed to assess the effect of hypoxia on FLS responses to the monokine interleukin-1 (IL-1) and to monocyte conditioned medium. Methods: FLS obtained from serial cultures of synovial fluid aspirates were treated with IL-1 or monocyte conditioned medium, under normoxia and hypoxia. Results: In hypoxia, transcription of cyclooxygenase 2 (COX-2), expression of COX-2 protein, and production of COX-2-derived eicosanoids and matrix metalloproteinase (MMP) activity by FLS were all increased in response to IL-1. In contrast to our recent observations concerning monocytes, there was no change in COX-2 message stability and cytosolic phospholipase A2 activity in the FLS under hypoxia. Treatment of monocyte conditioned medium with an IL-1 blocking antibody showed that most of the effect of the conditioned medium was attributable to IL-1. Conclusion: The findings suggest that hypoxia is an important factor in aggravating the inflammatory lesion in RA, through increased production of COX-2-derived nociceptive eicosanoids and increased release of tissue-damaging MMPs.Maryanne Demasi, Leslie G. Cleland, Rebecca J. Cook-Johnson, Michael J. Jame