ROLE OF CYTOKINES, TYROSINE KINASE, AND PROTEIN-KINASE-C ON PRODUCTION OF SUPEROXIDE AND INDUCTION OF SCAVENGING ENZYMES IN HUMAN-LEUKOCYTES

We investigated the effects of proximal modulators of cytokines, tyros ine kinase (TK), and protein kinase C (PKC) on reactive oxygen species (ROS) generation and the induction of scavenging enzymes, superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) of huma n neutrophils and lymphocytes, by using IL1-alpha, TNF-alpha, and IFN- gamma and neutralizing antibodies to these cytokines. Inhibitors of TK (ST638 and herbimycin) or PKC (H-7, calphostin, and staurosporine) wer e also used. The results revealed that both O-2(-) generation stimulat ed by five different agents (opsonized zymosan, A23187, PAF, PMA, and fMLP) and the inductions of all three scavenging enzymes were potentia ted by priming with TNF-alpha. In contrast, both O-2(-) generation and enzyme induction were attenuated by priming with IL1-alpha, with the exception of PMA-stimulated O-2(-) generation. IFN-gamma decreased O-2 (-) generation but increased scavenging enzyme induction. Antibodies t o all three cytokines and all the TK and PKC inhibitors decreased O-2( -) Stimulated by most agents, but markedly enhanced O-2(-) levels stim ulated by PAF. Induction of all three enzymes was enhanced equally by low concentrations of each of the three anticytokine antibodies, while each of the TK or PKC inhibitors decreased induction of SOD and GSH-P x and increased catalase induction. These results suggest that both RO S generation and scavenging enzyme induction are controlled in complex ways by the actions of these three proximal mediators. This supports our hypothesis that disturbances in the regulation of early events of cell activation can lead to oxidative tissue injury. (C) 1996 Academic Press, Inc.