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Involvement of BLT1 Endocytosis and Yes Kinase Activation in Leukotriene B₄-Induced Neutrophil Degranulation¹

Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada

One of the important biological activities of human neutrophils is degranulation, which can be induced by leukotriene B₄ (LTB₄). Here we investigated the intracellular signaling events involved in neutrophil degranulation mediated by the high affinity LTB₄ receptor, BLT1. Peripheral blood neutrophils as well as the promyeloid PLB-985 cell line, stably transfected with BLT1 cDNA and differentiated into a neutrophil-like cell phenotype, were used throughout this study. LTB₄-induced enzyme release was inhibited by 50–80% when cells were pretreated with the pharmacological inhibitors of endocytosis sucrose, Con A and NH₄Cl. In addition, transient transfection with a dominant negative form of dynamin (K44A) resulted in 70% inhibition of ligand-induced degranulation. Pretreating neutrophils or BLT1-expressing PLB-985 cells with the Src family kinase inhibitor PP1 resulted in a 30–60% inhibition in BLT1-mediated degranulation. Yes kinase, but not c-Src, Fgr, Hck, or Lyn, was found to exhibit up-regulated kinase activity after LTB₄ stimulation. Moreover, BLT1 endocytosis was found to be necessary for Yes kinase activation in neutrophils. LTB₄-induced degranulation was also sensitive to inhibition of PI3K. In contrast, it was not affected by inhibition of the mitogen-activated protein kinase MEK kinase, the Janus kinases, or the receptor tyrosine kinase epidermal growth factor receptor or platelet-derived growth factor receptor. Taken together, our results suggest an essential role for BLT1 endocytosis and Yes kinase activation in LTB₄-mediated degranulation of human neutrophils.

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