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Am. J. Respir. Cell Mol. Biol., Volume 18, Number 1, January, 1998 136-144

Protein Kinase C Inhibition Enhances Platelet-activating Factor-induced Eicosanoid Production in Human Eosinophils

Gordon Dent, Nilda M. Muñoz, Elke Rühlmann, Xiangdong Zhu, Alan R. Leff, Helgo Magnussen, and Klaus F. Rabe

Krankenhaus Grosshansdorf, Zentrum für Pneumologie und Thoraxchirurgie, LVA Hamburg, Grosshansdorf, Germany; and Section of Pulmonary and Critical Care Medicine, Department of Medicine, and Committee on Cell Physiology, Division of Biological Sciences, University of Chicago, Chicago, Illinois

Previous investigations have suggested that protein kinase C (PKC) may regulate guinea pig eosinophil responses through a suppressive "negative feedback" mechanism. Using the selective PKC inhibitors bisindolylmaleimide I (Bis I, GF 109203X) and calphostin C, we examined the role of PKC in platelet-activating factor (PAF)-induced respiratory burst and generation of arachidonic acid metabolites in human peripheral blood eosinophils. Bis I inhibited PAF-induced generation of superoxide anion with substantially lower potency (geometric mean IC50 = 1.41 µM, 95% CI 0.94 -2.11 µM) than it exhibited against responses to the phorbol esters 4-beta -phorbol 12-myristate 13-acetate (PMA; IC50 = 0.25 µM, 0.09-0.72 µM; P < 0.01) and 4-beta -phorbol 12,13-dibutyrate (IC50 = 0.48 µM, 0.20-1.14 µM; P < 0.05). The production of thromboxane (measured as TxB2) induced by 1 µM PAF was increased significantly by Bis I at concentrations of 1 µM (162 ± 7.5% of control PAF response; P < 0.01) and 10 µM (194 ± 17%; P < 0.001); TxB2 release induced by PMA was unaffected by concentrations of Bis I up to 1 µM and inhibited by 10 µM Bis I (48 ± 11%; P < 0.05). Bis I (1 µM) significantly increased both thromboxane and leukotriene C4 (LTC4) production induced by 2 µM (P < 0.01 and P < 0.05, respectively) or 20 µM PAF (both P < 0.001). The actions of Bis I on PAF-stimulated thromboxane and leukotriene production were mimicked by a second PKC inhibitor, calphostin C, whereas the non-PKC-inhibitory analog, bisindolylmaleimide V, caused no enhancement of TxB2 or LTC4 production. The increase in intracellular free calcium induced by 1 µM PAF was heightened and prolonged in cells pre-treated with 1 µM Bis I or 1 µM calphostin C (peak increase, P < 0.05 for both drugs; level 60 s after addition of PAF, P < 0.001 and P < 0.05 for Bis I and calphostin C, respectively; time to return to 50% of peak, P < 0.05 for Bis I). We conclude that PKC inhibition causes augmentation of thromboxane and LTC4 production in PAF-stimulated human eosinophils despite suppressing respiratory burst activity, indicating that different signaling pathways predominate in these two responses and that PKC mediates a suppression of an early stage in an alternative pathway of activation.




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