EFFECTS OF TENIDAP ON CA2+- AND PROTEIN-KINASE C-MEDIATED PROTEIN-PHOSPHORYLATION, ACTIVATION OF THE ARACHIDONATE-MOBILIZING PHOSPHOLIPASE A(2) AND SUBSEQUENT EICOSANOID FORMATION IN MACROPHAGES

Tenidap is a novel antirheumatic drug which combines non-steroidal antiinflammatory drug-like cyclooxygenase inhibition with cytokine modulating qualities in rheumatoid arthritis. We show herein that tenidap (5-20 mu M) inhibited protein kinase C-mediated signalling leading to release of arachidonate in mouse macrophages by interfering with the up-regulation of the 85 kDa arachidonate-mobilizing phospholipase A(2), although it did not inhibit this enzyme directly. The Ca2+-mediated activation of arachidonate mobilization was inhibited only at higher concentrations (20-40 mu M). Studies of protein phosphorylation indicated that tenidap in itself was capable of inducing the phosphorylation of several protein bands through interaction with intracellular protein kinases and/or phosphatases. Importantly, tenidap inhibited both arachidonate release and the increase in intracellular protein phosphorylation when the cells were stimulated with zymosan. We propose that the main inhibitory influence of tenidap on the macrophage signalling investigated here is exerted at some level between protein kinase C and the 85 kDa phospholipase A(2) and quite possibly also at the receptor-linked activation of phospholipase C.