Modulation of interleukin-1-induced alterations in cartilage proteoglycan metabolism by activation of protein kinase C.
Interleukin-1 (IL-1) stimulates proteoglycan degradation and prostaglandin E2 (PGE2) release and inhibits proteoglycan synthesis by cartilage in organ culture. Addition of the protein kinase C (PKC) activator, mezerein, resulted in the concentration-dependent inhibition of IL-1 activity on proteoglycan metabolism. Similar effects were seen with other compounds which stimulated PKC, such as teleocidin B4 and phorbol dibutyrate (PDBu), but not with a phorbol analog that is inactive in stimulating PKC. Simultaneous addition of the PKC antagonist, staurosporine, blocked the mezerein-induced inhibition of IL-1 activity on both proteoglycan degradation and synthesis in a concentration-related manner. In contrast to its inhibition of the effect of IL-1 on proteoglycan metabolism, mezerein did not block the release of PGE2 by cartilage in response to IL-1 but caused a synergistic stimulation of PGE2 release. Importantly, in cultures made deficient in PKC by prolonged incubation with PDBu, the effects of this PKC agonist on proteoglycan breakdown and PGE2 were blocked, while stimulation by IL-1 persisted. These data indicate that the effects of IL-1 on proteoglycan metabolism and prostaglandin production are mediated by an intracellular signal distinct from PKC and suggest that activation of PKC in chondrocytes may play a role in modulating the action of IL-1 on proteoglycan metabolism.
Arner
E C
EC
Cancer and Inflammatory Diseases Section, Du Pont Merck Pharmaceuticals Company, Inc., Wilmington, Delaware 19880-0400.
Pratta
M A
MA
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002356:Cartilage / Q000378:metabolism*; D002417:Cattle; D015232:Dinoprostone / Q000378:metabolism; D004224:Diterpenes; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology*; D009924:Organ Culture Techniques; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011509:Proteoglycans / Q000378:metabolism*; D019311:Staurosporine; D013729:Terpenes / Q000494:pharmacology
D000470:Alkaloids; D002273:Carcinogens; D004224:Diterpenes; D007375:Interleukin-1; D010703:Phorbol Esters; D011509:Proteoglycans; D013729:Terpenes; C008876:phorbol-12,13-didecanoate; C011309:mezerein; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D019311:Staurosporine; D015232:Dinoprostone