Effects of tenidap on Ca(2+)- and protein kinase C-mediated protein phosphorylation, activation of the arachidonate-mobilizing phospholipase A2 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 microM) 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 A2, although it did not inhibit this enzyme directly. The Ca(2+)-mediated activation of arachidonate mobilization was inhibited only at higher concentrations (20-40 microM). 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 A2 and quite possibly also at the receptor-linked activation of phospholipase C.
Bondeson
J
J
Department of Physiological Chemistry, Lund University, Sweden.
Sundler
R
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D000001:Calcimycin / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism*; D015777:Eicosanoids / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D000078183:Oxindoles; D010703:Phorbol Esters / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D015054:Zymosan / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D015777:Eicosanoids; D007211:Indoles; D000078183:Oxindoles; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D011506:Proteins; D000001:Calcimycin; D015054:Zymosan; C062866:tenidap; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D002118:Calcium