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

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 1 beta (rhIL-1 beta) (100 ng/ml) and/or indomethacin (0.1, 1, 10 mu M) and diclofenac (0.1, 1, 10 mu M) and/or prostaglandin E-2 (PGE(2)) (1, 10 mu M) for 72 h. Methods: The amounts of TIMP-1, proMMP-1 and PGE(2) was measured by enzyme linked immunosorbent assay (ELISA). Statistical significance was tested with Student's t-test and Dunnett test. Results: RhIL-1 beta augments the production of TIMP-1 and proMMP-1 in synovial fibroblasts from RA patients, and this IL-l-induced production of TIMP-1 and proMMP-1 was further enhanced by treatment with the cyclooxygenase inhibitors, indomethacin and diclofenac. Exogenous PGE(2) significantly suppresses indomethacin-and diclofenacenhanced TIMP-1 and proMMP-1 production. Conclusion: PGE(2) 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 PGE(2) production in inflammation.