Canetti Claudio, Hu Bin, Curtis Jeffrey L, Peters-Golden Marc
Division of Pulmonary and Critical Care Medicine, 6301 MSRB III, University of Michigan Medical Center, Ann Arbor, MI 48109-0642, USA.
Blood. 2003 Sep 1;102(5):1877-83. doi: 10.1182/blood-2003-02-0534. Epub 2003 May 1.
Macrophages are called upon to ingest both IgG-coated targets and apoptotic cells. Important roles for tyrosine kinase Syk and leukotriene B4 (LTB4) are recognized in FcgammaR-mediated phagocytosis. Here we evaluated the roles of Syk and LTB4 in macrophage phagocytosis of apoptotic thymocytes versus IgG-coated erythrocytes. Macrophage ingestion of apoptotic thymocytes was not influenced by exogenous or endogenous LTB4 nor associated with Syk activation (phosphorylation). By contrast, LTB4 dose-dependently amplified FcgammaR-mediated phagocytosis as well as Syk activation. Furthermore, a role for endogenous LTB4 in Syk activation during FcgammaR-mediated phagocytosis was demonstrated using pharmacologic and genetic abrogation of 5-lipoxygenase. LTB4 was unique among 5-lipoxygenase products in this regard, since LTD4 and 5-hydroxyeicosatetraenoic acid (HETE) were unable to amplify Syk activation in response to FcgammaR engagement. Ca2+ chelation studies revealed that FcgammaR-mediated Syk activation as well as LTB4 amplification thereof was Ca2+ regulated. These 2 parallel phagocytic processes therefore exhibit initial divergence in signal transduction events, with Syk activation being an LTB4-regulated event in FcgammaR-mediated but not apoptotic cell ingestion. As LTB4 is an important proinflammatory product of macrophages, we speculate that this divergence evolved to permit FcgammaR-mediated phagocytosis to proceed in an inflammatory milieu, while apoptotic cell clearance is noninflammatory.
巨噬细胞需要摄取IgG包被的靶标和凋亡细胞。酪氨酸激酶Syk和白三烯B4（LTB4）在FcγR介导的吞噬作用中发挥重要作用。在此，我们评估了Syk和LTB4在巨噬细胞吞噬凋亡胸腺细胞与IgG包被的红细胞过程中的作用。巨噬细胞对凋亡胸腺细胞的摄取不受外源性或内源性LTB4的影响，也与Syk激活（磷酸化）无关。相比之下，LTB4呈剂量依赖性地增强FcγR介导的吞噬作用以及Syk激活。此外，通过对5-脂氧合酶进行药理学和遗传学阻断，证明了内源性LTB4在FcγR介导的吞噬作用过程中对Syk激活的作用。在这方面，LTB4在5-脂氧合酶产物中是独特的，因为LTD4和5-羟基二十碳四烯酸（5-HETE）不能增强FcγR结合后Syk的激活。Ca2+螯合研究表明，FcγR介导的Syk激活及其LTB4的增强作用均受Ca2+调节。因此，这两个平行的吞噬过程在信号转导事件中表现出初始差异，Syk激活在FcγR介导的吞噬作用中是LTB4调节的事件，但在凋亡细胞摄取中并非如此。由于LTB4是巨噬细胞的一种重要促炎产物，我们推测这种差异的进化是为了使FcγR介导的吞噬作用能够在炎症环境中进行，而凋亡细胞的清除则是非炎症性的。
