Interleukin-1 beta induction of tissue inhibitor of metalloproteinase (TIMP-1) is functionally antagonized by prostaglandin E2 in human synovial fibroblasts.
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-1 beta (IL-1 beta) and prostaglandin E2 (PGE2), 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, 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-1 beta induction of TIMP-1 mRNA. PGE2 also inhibited rhIL-1 beta-stimulated TIMP-1 mRNA expression and protein secretion in a dose-dependent fashion. The concentration of PGE2 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 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.
DiBattista
J A
JA
University of Montreal, Canada.
Pelletier
J P
JP
Zafarullah
M
M
Iwata
K
K
Martel-Pelletier
J
J
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D015152:Blotting, Northern; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D019311:Staurosporine; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000470:Alkaloids; D006023:Glycoproteins; D007375:Interleukin-1; D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013873:Thionucleotides; D019714:Tissue Inhibitor of Metalloproteinases; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D003994:Bucladesine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D017364:Collagenases; D008666:Metalloendopeptidases; D019311:Staurosporine; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate