title: A novel conformationally restricted protein kinase C inhibitor, Ro 31-8425, inhibits human neutrophil superoxide generation by soluble, particulate and post-receptor stimuli.
abstract: 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 Ca2+/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-receptor 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.
authors.affiliation: Department of Pharmacology, University College London, England.
authors.forename: R E
authors.initials: RE
authors.lastname: Muid
authors.forename: M M
authors.initials: MM
authors.lastname: Dale
authors.forename: P D
authors.initials: PD
authors.lastname: Davis
authors.forename: L H
authors.initials: LH
authors.lastname: Elliott
authors.forename: C H
authors.initials: CH
authors.lastname: Hill
authors.forename: H
authors.initials: H
authors.lastname: Kumar
authors.forename: G
authors.initials: G
authors.lastname: Lawton
authors.forename: B M
authors.initials: BM
authors.lastname: Twomey
authors.forename: J
authors.initials: J
authors.lastname: Wadsworth
authors.forename: S E
authors.initials: SE
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D002417:Cattle; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011487:Protein Conformation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011817:Rabbits; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D012995:Solubility; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D007211:Indoles; D008301:Maleimides; D011956:Receptors, Cell Surface; D013481:Superoxides; C071924:Ro 31-8425; D011493:Protein Kinase C; C064755:Ro 31-7549