Protein kinase C and chondrocyte activation

We have begun to examine the role of protein kinase C (PKC) in chondrocyte activation by interleukin-1 (IL-1) in search of a possible signal transduction mechanism. Untreated chondrocytes synthesised little or no collagenase or gelatinase and only modest amounts of prostaglandin E₂ (PGE₂), while IL-1 induced considerable amounts of these. An activator of PKC, phorbol myristate acetate (PMA), alone did not influence the synthesis of the metalloproteinases to any great degree, but enhanced PGE₂ production. Sphingosine and staurosporin, inhibitors of PKC, each eliminated the synergistic effect of PMA upon enzyme induction by high doses (10 U/ml) of IL-1, but failed to influence enzyme induction by this dose of IL-1 alone. However, a low dose (1 U/ml) of IL-1 in combination with these inhibitors was synergistic upon enzyme induction. Although these inhibitors reduced the synthesis of PGE₂ in response to PMA, synthesis of PGE₂ in response to both doses of IL-1 was greatly enhanced by the inhibitors. PMA, but not IL-1, enhanced the phosphorylation of an 80 K protein which is characteristic of PKC activity in certain types of cells. From these data, we conclude that PKC is unlikely to be involved in the induction of neutral metalloproteinases by IL-1, although once induction has occurred, PKC may modulate this effect. PKC may also act as regulator of PGE₂ synthesis, although this requires further investigation.