Effect of phorbol ester on the inhibition of proteoglycan synthesis induced by interleukin 1 and antiinflammatory drugs.

Low (2 ng/ml) and high (40 ng/ml) concentrations of the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (PMA) were tested for their effect on cultured bovine articular chondrocyte proteoglycan synthesis. In addition, we examined whether PMA could reverse interleukin 1 (IL-1) and nonsteroidal antiinflammatory drug (NSAID) induced inhibition of proteoglycan synthesis. Low concentrations of PMA stimulated proteoglycan synthesis by chondrocytes. High concentrations of PMA had no significant effect. IL-1 and high concentrations of NSAID inhibited proteoglycan production by chondrocytes. Low concentrations of PMA completely reversed IL-1 induced inhibition but did not significantly alter proteoglycan synthesis in the presence of antiinflammatory drugs. On the other hand, high concentrations of PMA had little effect on IL-1 induced inhibition but significantly potentiated the suppression of proteoglycan synthesis induced by 2 of the NSAID tested, indomethacin and flurbiprofen. Assay of PKC activity indicated that PKC levels were down-regulated by high but not by low concentrations of PMA. This suggests that different mechanisms were regulating the effects of low and high concentrations of PMA on proteoglycan synthesis. Although IL-1 and high concentrations of NSAID both suppress proteoglycan synthesis by chondrocytes, their different responses when coincubated with PMA suggest that they act through different pathways.