Interleukin‐1β induction of tissue inhibitor of metalloproteinase (TIMP‐1) is functionally antagonized by prostaglandin E2 in human synovial fibroblasts

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Abstract
Elevated levels of tissue inhibitor of metalloproteases‐1 (TIMP‐1) have been demonstrated in inflamed synovial membranes, and it is believed that the inhibitor may play a critical role in the regulation of connective tissue degradation. The present study was undertaken to define the cellular mechanism of action of the inflammatory mediators, interleukin‐1β (IL‐1β) and prostaglandin E2 (PGE2), in the control of TIMP‐1 synthesis and expression in human synovial fibroblasts. Recombinant human IL‐1β induced a time‐ and dose‐dependent saturable response in terms of TIMP‐1 mRNA expression (effective concentration for 50% maximal response, EC50 = 31.5 ± 3.3 pg/ml) and protein synthesis (EC50 = 30 ± 3.3 pg/ml). The protein kinase C (PKC) inhibitors, H‐7, staurosporine, and calphostin C, reversed the rhIL‐1β induction of TIMP‐1 mRNA. PGE2 also inhibited rhIL‐1β‐stimulated TIMP‐1 mRNA expression and protein secretion in a dose‐dependent fashion. The concentration of PGE2 necessary to block 50% of rhIL‐1β‐stimulated TIMP‐1 secretion, IC50, was 1.93 ng/ml (4.89 nM). Forskolin, and other stable derivatives of cAMP, mimicked, to a large extent, the effects of PGE2. The phorbol ester, PMA, up‐regulated considerably the mRNA expression of TIMP‐1 but had no effect on protein production. Calphostin C substantially reduced PMA‐activated TIMP‐1 expression. Staurosporine, calphostin C, H‐7, and substances that elevate cellular levels of cAMP, like PGE2, also reduced basal expression and synthesis of TIMP‐1. Taken together, the data suggest that PKA and C may mediate opposing effects in terms of TIMP‐1 expression and secretion in human synovial fibroblasts.

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