A novel conformationally restricted protein kinase C inhibitor, Ro 31-8425, inhibits human neutrophil superoxide generation by soluble, particulate and post-receptor stimuli.
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.
Muid
R E
RE
Department of Pharmacology, University College London, England.
Dale
M M
MM
Davis
P D
PD
Elliott
L H
LH
Hill
C H
CH
Kumar
H
H
Lawton
G
G
Twomey
B M
BM
Wadsworth
J
J
Wilkinson
S E
SE
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
D007211:Indoles; D008301:Maleimides; D011956:Receptors, Cell Surface; D013481:Superoxides; C071924:Ro 31-8425; D011493:Protein Kinase C; C064755:Ro 31-7549