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
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.


METHODS
Synovial fibroblasts from RA patients were used.


METHODS
The cells were treated with recombinant human interleukin 1 beta (rhIL-1 beta) (100 ng/ml) and/or indomethacin (0.1, 1, 10 microM) and diclofenac (0.1, 1, 10 microM) and/or prostaglandin E2 (PGE2) (1, 10 microM) 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-1 beta 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 diclofenacenhanced TIMP-1 and proMMP-1 production.


CONCLUSIONS
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.
Takahashi
S
S
Division of Rheumatology, St. Marianna University, School of Medicine, Kanagawa, Japan.
Inoue
T
T
Higaki
M
M
Mizushima
Y
Y
D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004792:Enzyme Precursors / Q000096:biosynthesis*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects* / Q000201:enzymology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
D016861:Cyclooxygenase Inhibitors; D004792:Enzyme Precursors; D007375:Interleukin-1; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D004008:Diclofenac; D017364:Collagenases; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone; D007213:Indomethacin