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

FEBS Letters

Dale, M.Maureen¹  Muid, Robert E.¹  Davis, Peter D.²  Wilkinson, Sandra E.²  Hill, Christopher H.²  Nixon, John S.²  Elliott, Lucy H.²  Lawton, Geoffrey²  Wadsworth, Julie²  Twomey, Breda M.¹  Kumar, Hari² 

[1] Department of Pharmacology, University College London, Gower Street, London, WC1E 6BT, England;Research Centre, Roche Products Ltd., Broadwater Road, Welwyn Garden City, AL7 3AY, England

关键词: Neutrophil;    Superoxide;    Protein kinase C;    Opsonized zymosan;    T-Cell proliferation;    Interleukin-2;    O2;    superoxide;    DAG;    diacylglycerol;    DiCk;    dioctanoylglycerol;    fMLP;    formyl-methionyl-leucyl-phenyl-alanine;    IP3;    inositol trisphosphate;    PDBu;    phorbol dibutyrate;    PIP2;    phosphatidyl-inositol bisphosphate;    PLC;    phospholipase C;    PLD;    phospholipase D;    PKA;    protein kinase A;    PKC;    protein kinasc C;    TPA;    12-O-tetradecanoylphorbol 13-acetate;   

DOI  :  10.1016/0014-5793(91)81178-B

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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-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.

【 授权许可】

Unknown