Modulation of synovial fibroblast plasminogen activator and plasminogen activator inhibitor production by protein kinase C.
Phorbol myristate acetate (PMA) added to human synovial fibroblast cultures caused a dose-dependent increase in the production of plasminogen activator inhibitor-type 1 (PAI-1). In addition, PMA inhibited endogenous and interleukin-1 (IL-1) induced plasminogen activator (PA) activity, while increasing mRNA PAI-1 levels. Other protein kinase C (PKC) activators, mezerein and teleocidin B4, caused similar effects. The simultaneous addition of the PKC antagonists, H-7 or staurosporine, prevented the inhibition of PA activity by PMA. This study shows that activation of PKC inhibits PA and stimulates PAI production in human synovial fibroblasts. These results suggest that activation of PKC may play an important role in regulating increased PA production associated with joint destruction in rheumatoid arthritis (RA).
Uhl
J
J
Department of Inflammation, Sterling Research Group, Rennselaer, NY 12144.
Newton
R C
RC
Gross
J L
JL
Rommi
W
W
Mochan
E
E
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D002478:Cells, Cultured; D004224:Diterpenes; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008235:Lyngbya Toxins / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010960:Plasminogen Activators / Q000378:metabolism*; D015849:Plasminogen Inactivators / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D019311:Staurosporine; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000470:Alkaloids; D004224:Diterpenes; D007375:Interleukin-1; D007546:Isoquinolines; D008235:Lyngbya Toxins; D010879:Piperazines; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D013729:Terpenes; C022176:teleocidins; C011309:mezerein; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D010960:Plasminogen Activators; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate