Differential kinase requirement for enhancement of FcγR-mediated phagocytosis in alveolar macrophages by leukotriene B4 vs. D4

In alveolar macrophages, leukotriene (LT) B4 and cysteinyl LTs (LTC4, LTD4 and LTE4) both enhance Fcγ receptor (FcγR)-mediated phagocytosis. In the present study we investigated the role of specific PKC isoforms (PKC-α and -δ), the MAP kinases p38 and ERK 1/2, and PI3K in mediating the potentiation of FcγR-mediated phagocytosis induced by addition of leukotrienes to the AMs. It was found that exogenously added LTB4 and LTD4 both enhanced PKC-δ and -α phosphorylation during FcγR engagement. Studies with isoform-selective inhibitors indicated that exogenous LTB4 effects were dependent on both PKC-α and -δ, while LTD4 effects were exclusively due to PKC-δ activation. Although both exogenous LTB4 and LTD4 enhanced p38 and ERK 1/2 activation, LTB4 required only ERK 1/2, while LTD4 required only p38 activation. Activation by both LTs was dependent on PI3K activation. Effects of endogenous LTs on kinase activation were also investigated using selective LT receptor antagonists. Endogenous LTB4 contributed to FcγR-mediated activation of PKC-α, ERK 1/2 and PI3K, while endogenous cysLTs contributes to activation of PKC-δ, p38 and PI3K. Taken together, our data show that the capacities of LTB4 and LTD4 to enhance FcγR-mediated phagocytosis reflect their differential activation of specific kinase programs.