Modulation of neutrophil superoxide generation by inhibitors of protein kinase C, calmodulin, diacylglycerol and myosin light chain kinases, and peptidyl prolyl cis-trans isomerase.
To assess the role of protein kinase C (PKC) in the respiratory burst of adherent human polymorphonuclear leukocytes (PMNL), reduction of ferricytochrome C by cells triggered with a phorbol ester (PMA), ionophore A23187, serum-treated zymosan (STZ) or three lipid derivatives, 3-decanoyl-sn-glycerol (G-3-OCOC9), (R,R)-1,4-diethyl-2-O-decyl-L-tartrate (Tt-2-OC10) and 3-decyloxy-5-hydroxymethylphenol (DHP) was examined in a microtiter plate procedure in the presence of inhibitors of PKC and, for comparison, inhibitors of calmodulin, diacylglycerol and myosin light chain kinases and the peptidyl-prolyl cis-trans isomerase activity of fujiphilin. 1) Of the protein kinase inhibitors examined, Ro 31-7549 and staurosporine reduced responses to all stimuli except possibly STZ; in contrast, K252a and the myosin light chain kinase inhibitors ML-7 and ML-9 blocked responses to A23187 and STZ better than those triggered by PMA. H-7 reduced responses to A23187, DHP and G-3-OCOC9, and calphostin, palmitoyl carnitine, sphingosine and the multifunctional drugs TMB-8 and W-7 reduced A23187; they also, when examined, reduced decane derivative-induced O2- production more effectively than PMA- and STZ-triggered responses. Polymyxin B, 4 alpha-PMA and retinal displayed no inhibitory capacity. 2) Of the selective calmodulin antagonists, CGS 9343B, Ro 22-4839 and calmidazolium did not inhibit the oxidative response irrespective of the stimulus used, whereas metofenazate reduced those evoked by A23187, DHP, G-3-OCOC9 and STZ.(ABSTRACT TRUNCATED AT 250 WORDS)
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D001491:Basophils / Q000187:drug effects / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002227:Carbazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D019852:Diacylglycerol Kinase; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D026121:Indole Alkaloids; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D002147:Calmodulin; D002227:Carbazoles; D002352:Carrier Proteins; D026121:Indole Alkaloids; D011744:Pyrimidinones; D013844:Thiazoles; D013481:Superoxides; C047505:R 59022; C049985:staurosporine aglycone; D010770:Phosphotransferases; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D009219:Myosin-Light-Chain Kinase; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D013755:Tetradecanoylphorbol Acetate; D016559:Tacrolimus