INTERLEUKIN-1-BETA INDUCTION OF TISSUE INHIBITOR OF METALLOPROTEINASE (TIMP-1) IS FUNCTIONALLY ANTAGONIZED BY PROSTAGLANDIN E(2) IN HUMAN SYNOVIAL FIBROBLASTS

被引:19
作者
DIBATTISTA, JA
PELLETIER, JP
ZAFARULLAH, M
IWATA, K
MARTELPELLETIER, J
机构
[1] UNIV MONTREAL, MONTREAL, PQ H2L 4K8, CANADA
[2] NOTRE DAME HOSP, LOUIS CHARLES SIMARD RES CTR, MONTREAL, PQ H2L 4K8, CANADA
[3] FUJI CHEM IND CO LTD, RES LABS, TAKAOKA, TOYAMA 933, JAPAN
关键词
INTERLEUKIN-1; PROSTAGLANDIN E(2); TIMP-1; HUMAN SYNOVIAL FIBROBLASTS;
D O I
10.1002/jcb.240570406
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Elevated levels of tissue inhibitor of metalloproteases-l (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-1 beta (IL-1 beta) and prostaglandin E(2) (PGE(2)), in the control of TIMP-1 synthesis and expression in human synovial fibroblasts. Recombinant human IL-1 beta 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-1 beta induction of TIMP-1 mRNA. PGE(2) also inhibited rhIL-1 beta-stimulated TIMP-1 mRNA expression and protein secretion in a dose-dependent fashion. The concentration of PGE(2) necessary to block 50% of rhIL-1 beta-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 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 oi TIMP-1 expression and secretion in human synovial fibroblasts. (C) 1995 Wiley-Liss, Inc.
引用
收藏
页码:619 / 629
页数:11
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