Negative Regulation of Class IA Phosphoinositide 3-kinase by Protein Kinase Cδ Limits Fcγ Receptor-mediated Phagocytosis in Macrophages

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Stimulation of macrophages by various ligands results in the activation of both phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC). Here, we showed that PKCδ selectively inhibits class IA PI3K. Prior exposure of macrophages to a PKC activator, phorbol 12-myristate 13-acetate (PMA) inhibited the PI3K activation induced by the Fcγ receptor (FcγR) ligation but not that induced by C5a. Prolonged PKC inhibition by GF109203X increased the basal PI3K activity of quiescent macrophages. The effect of the PKC inhibitor can be observed in macrophages from mice lacking class IB PI3K (p110γ). Thus PKC was suggested to selectively attenuate the class IA activity. Chronic PKC activation by PMA induced PKCδ degradation and Akt activation. Enhancement of the basal Akt actvity was also observed in cells stably deficient in PKCδ prepared by shRNA technique. FcγR-mediated phagocytosis was dramatically increased in these cells. Thus it is suggested that inactivation of class IA PI3K by PKCδ is functioning in regulation of FcγR-mediated phagocytosis.
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2009-01-01