A novel conformationally restricted protein kinase C inhibitor, Ro 31-8425, inhibits human neutrophil superoxide generation by soluble, particulate and post-receptor stimuli

• Published in: FEBS letters Vol. 293; no. 1; pp. 169 - 172
• Main Authors: Muid, Robert E., Dale, M.Maureen, Davis, Peter D., Elliott, Lucy H., Hill, Christopher H., Kumar, Hari, Lawton, Geoffrey, Twomey, Breda M., Wadsworth, Julie, Wilkinson, Sandra E., Nixon, John S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 1991; Elsevier
• Subjects: 12-O-tetradecanoylphorbol 13-acetate; Animals; Biological and medical sciences; Brain - enzymology; Cattle; Cell physiology; DAG; diacylglycerol; DiCk; dioctanoylglycerol; Effects of physical and chemical agents; fMLP; formyl-methionyl-leucyl-phenyl-alanine; Fundamental and applied biological sciences. Psychology; Humans; Indoles - pharmacology; inositol trisphosphate; Interleukin-2; IP3; Maleimides - pharmacology; Molecular and cellular biology; Neutrophil; Neutrophils - drug effects; Neutrophils - enzymology; Neutrophils - metabolism; Opsonized zymosan; PDBu; phorbol dibutyrate; phosphatidyl-inositol bisphosphate; phospholipase C; phospholipase D; PIP2; PKA; PKC; PLC; PLD; Protein Conformation; protein kinasc C; protein kinase A; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - chemistry; Rabbits; Rats; Receptors, Cell Surface - drug effects; Receptors, Cell Surface - metabolism; Respiratory Burst - drug effects; Solubility; Superoxide; Superoxides - antagonists & inhibitors; Superoxides - blood; T-Cell proliferation; TPA; O 2; PIP 2; Protein kinase C; PDBu; Interleukin-2; fMLP; TPA; PLC; DiC k; PKA; PLD; PKC; Superoxide; DAG; IP 3; Neutrophil; T-Cell proliferation; Opsonized zymosan; Human; Cell proliferation; Signal transduction; Hyperoxides; Interleukin 2; Enzyme; T-Lymphocyte; Enzyme inhibitor; Biological activity
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/0014-5793(91)81178-B

A novel,
bis-indolylmaleimide, Ro 31-8425, bearing a conformationally restricted side chain, inhibits protein kinase C isolated from rat brain and human neutrophils with a high degree of selectivity over cAMP-dependent kinase and Ca
2−/calmodulin-dependent kinase. It also inhibits phorbol ester-induced intracellular events known to be mediated by protein kinase C(p47 phosphorylation in intact platelets, CD3 and CD4 down-regulation in T-cells). Ro 31-8425 inhibited superoxide generation in human neutrophils activated by both receptor stimuli (formyl-methionyl-leucylphenylalanine, opsonized zymosan. IgG and heat aggregated IgG) and post-rcceptor stimuli (1,2-dioctanoylglycerol and fluoride). The compound also blocked antigen driven, but not IL-2 induced, T-cell proliferation. These results support a central role for protein kinase C in the activation of the respiratory burst and antigen-driven T-cell proliferation.