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 f or their effect on cultured bovine articular chondrocyte proteoglycan synthesis. In addition, we examined whether PMA could reverse interleu kin 1 (IL-1) and nonsteroidal antiinflammatory drug (NSAID) induced in hibition of proteoglycan synthesis. Low concentrations of PMA stimulat ed proteoglycan synthesis by chondrocytes. High concentrations of PMA had no significant effect. IL-1 and high concentrations of NSAID inhib ited proteoglycan production by chondrocytes. Low concentrations of PM A completely reversed IL-1 induced inhibition but did not significantl y alter proteoglycan synthesis in the presence of antiinflammatory dru gs. 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, indometha cin 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 synthes is by chondrocytes, their different responses when coincubated with PM A suggest that they act through different pathways.