Role of Cytokines, Tyrosine Kinase, and Protein Kinase C on Production of Superoxide and Induction of Scavenging Enzymes in Human Leukocytes

• Published in: Clinical immunology and immunopathology 1996-06, Vol.79 (3), p.303-313
• Main Authors: Niwa, Y., Ozaki, Y., Kanoh, T., Akamatsu, H., Kurisaka, M.
• Format: Article
• Language: English
• Subjects: Adult; Analysis of the immune response. Humoral and cellular immunity; Biological and medical sciences; Bleomycin - pharmacology; Calcimycin - pharmacology; Catalase - metabolism; Cytokines - physiology; Enzyme Induction - drug effects; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Glutathione Peroxidase - metabolism; Humans; Immunobiology; Interferon-gamma - metabolism; Interleukin-1 - metabolism; Lymphocytes - physiology; Male; Middle Aged; Miscellaneous; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Neutrophils - physiology; Platelet Activating Factor - physiology; Protein Kinase C - physiology; Protein-Tyrosine Kinases - physiology; Regulatory factors and their cellular receptors; Respiratory Burst; Superoxide Dismutase - metabolism; Superoxides - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0090-1229; 1090-2341
• DOI: 10.1006/clin.1996.0083

We investigated the effects of proximal modulators of cytokines, tyrosine 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 human neutrophils and lymphocytes, by using IL1-α, TNF-α, and IFN-γ and neutralizing antibodies to these cytokines. Inhibitors of TK (ST638 and herbimycin) or PKC (H-7, calphostin, and staurosporine) were also used. The results revealed that both O−2generation stimulated by five different agents (opsonized zymosan, A23187, PAF, PMA, and fMLP) and the inductions of all three scavenging enzymes were potentiated by priming with TNF-α. In contrast, both O−2generation and enzyme induction were attenuated by priming with IL1-α, with the exception of PMA-stimulated O−2generation. IFN-γ decreased O−2generation but increased scavenging enzyme induction. Antibodies to all three cytokines and all the TK and PKC inhibitors decreased O−2stimulated by most agents, but markedly enhanced O−2levels stimulated 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-Px and increased catalase induction. These results suggest that both ROS 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.