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Interleukin‐1β induction of tissue inhibitor of metalloproteinase (TIMP‐1) is functionally antagonized by prostaglandin E 2 in human synovial fibroblasts
Author(s) -
Dibattista John A.,
Pelletier JeanPierre,
Zafarullah Muhammad,
Iwata Kazushi,
MartelPelletier Johanne
Publication year - 1995
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.240570406
Subject(s) - calphostin c , protein kinase c , staurosporine , forskolin , calphostin , prostaglandin e2 , protein kinase a , chemistry , microbiology and biotechnology , tissue inhibitor of metalloproteinase , endocrinology , medicine , biology , kinase , biochemistry , stimulation , matrix metalloproteinase
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 E 2 (PGE 2 ), 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, EC 50 = 31.5 ± 3.3 pg/ml) and protein synthesis (EC 50 = 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. PGE 2 also inhibited rhIL‐1β‐stimulated TIMP‐1 mRNA expression and protein secretion in a dose‐dependent fashion. The concentration of PGE 2 necessary to block 50% of rhIL‐1β‐stimulated TIMP‐1 secretion, IC 50 , was 1.93 ng/ml (4.89 nM). Forskolin, and other stable derivatives of cAMP, mimicked, to a large extent, the effects of PGE 2 . 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 PGE 2 , 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.