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Synergistic Effect of Type II Phospholipase A₂ and Platelet-Activating Factor on Mac-1 Surface Expression and Exocytosis of Gelatinase Granules in Human Neutrophils: Evidence for the 5-Lipoxygenase-Dependent Mechanism

Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Tsukuba, Ibaraki, Japan

Stimulation of human neutrophils with inflammatory mediators such as TNF- or platelet-activating factor (PAF) induces translocation of adhesion molecule Mac-1 (CD11b/CD18) from secretory vesicles to the plasma membrane. Type II phospholipase A₂ (PLA₂-II) also induces translocation of Mac-1 from secretory vesicles. However, there are more Mac-1 molecules in gelatinase granules and specific granules than in secretory vesicles. Therefore, different combinations of PLA₂-II and other mediators were examined for their ability to induce gelatinase granules and specific granules to induce Mac-1 surface expression. The combination of PLA₂-II and PAF synergistically increased Mac-1 surface expression, and the effect was greater than the combinations of PLA₂-II with TNF-, IL-8, or FMLP. Additionally, the combination of PLA₂-II and PAF induced exocytosis of both secretory vesicles and gelatinase granules, which did not occur with either PLA₂-II alone or PAF alone. The induction was accompanied by marked production of leukotriene B₄. AA861, an inhibitor of 5-lipoxygenase, did not inhibit exocytosis of secretory vesicles but did inhibit exocytosis of gelatinase granules and decrease Mac-1 surface expression. It was also found that Ca²⁺ influx is essential for 5-lipoxygenase activation, because Ni²⁺, which blocks the influx of extracellular Ca²⁺, inhibited the production of leukotriene B₄. These results suggest that stimulation by the combination of PLA₂-II and PAF, unlike stimulation by each mediator alone, causes exocytosis of gelatinase granules via the 5-lipoxygenase pathway, resulting in a synergistic increase in neutrophil Mac-1 surface expression during inflammatory processes.

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