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

In alveolar macrophages, leukotriene (IT) B-4 and cysteinyl LTs (LTC4, LTD4 and LTE4) both enhance Fc gamma receptor (Fc gamma R)-mediated phagocytosis. In the present study we investigated the role of specific PKC isoforms (PKC-alpha and -delta), the MAP kinases p38 and ERK 1/2, and PI3K in mediating the potentiation of Fc gamma R-mediated phagocytosis induced by addition of leukotrienes to the AMs. It was found that exogenously added LTB4 and LTD4 both enhanced PKC-delta and -alpha phosphorylation during Fc gamma R engagement. Studies with isoform-selective inhibitors indicated that exogenous LTB4 effects were dependent on both PKC-alpha and -delta, while LTD4 effects were exclusively due to PKC-delta 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 Fc gamma R-mediated activation of PKC-alpha, ERK 1/2 and PI3K, while endogenous cysLTs contributes to activation of PKC-delta, p38 and PI3K. Taken together, our data show that the capacities of LTB4 and LTD4 to enhance Fc gamma R-mediated phagocytosis reflect their differential activation of specific kinase programs. (C) 2008 Elsevier Ltd. All rights reserved.