Cyclooxygenase inhibitors enhance the production of tissue inhibitor-1 of metalloproteinases (TIMP-1) and pro-matrix metalloproteinase 1 (proMMP-1) in human rheumatoid synovial fibroblasts

Abstract.

Objective and Design: We investigated the influence of cyclooxygenase inhibitors against the production of tissue inhibitor-1 of metalloproteinases (TIMP-1) and pro-matrix metalloproteinase 1 (proMMP-1) in rheumatoid arthritis (RA) synoviocytes.¶Material: Synovial fibroblasts from RA patients were used.¶Treatment: The cells were treated with recombinant human interleukin 1β (rhIL-1β) (100 ng/ml) and/or indomethacin (0.1, 1, 10 μM) and diclofenac (0.1, 1, 10 μM) and/or prostaglandin E₂ (PGE₂) (1, 10 μM) for 72 h.¶Methods: The amounts of TIMP-1, proMMP-1 and PGE₂ was measured by enzyme linked immunosorbent assay (ELISA). Statistical significance was tested with Student's t-test and Dunnett test.¶Results: RhIL-1β augments the production of TIMP-1 and proMMP-1 in synovial fibroblasts from RA patients, and this IL-1-induced production of TIMP-1 and proMMP-1 was further enhanced by treatment with the cyclooxygenase inhibitors, indomethacin and diclofenac. Exogenous PGE₂ significantly suppresses indomethacin- and diclofenac-enhanced TIMP-1 and proMMP-1 production.¶Conclusion: PGE₂ down-regulates the production of TIMP-1 and proMMP-1 in RA synoviocytes, and cyclooxygenase inhibitors regulate the production of TIMP-1 and proMMP-1 through the inhibition of PGE₂ production in inflammation.