Allen Lee Ann H, Allgood J Aaron
Department of Medicine and The Inflammation Program, The University of Iowa and The Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
Curr Biol. 2002 Oct 15;12(20):1762-6. doi: 10.1016/s0960-9822(02)01216-2.
Phagocytosis is a rapid actin-dependent endocytic process used by macrophages and neutrophils to ingest and kill microorganisms. Perturbation of phagocytosis is central to the ability of some pathogenic microbes to cause disease, and we demonstrated previously that the ulcerogenic bacterium Helicobacter pylori (Hp) actively retards its uptake by macrophages and subsequently persists inside novel vacuoles called megasomes. Neither the receptor that mediates Hp binding nor the signaling pathways that regulate bacterial engulfment have been defined. Nevertheless, the fact that other phagocytic stimuli do not exhibit delayed phagocytosis suggests that Hp may be ingested by a unique mechanism. We now show that Hp transiently activated protein kinase C (PKC) in macrophages and that atypical PKCzeta and novel PKC(epsilon), but not conventional PKC(alpha), accumulated on forming phagosomes. Pharmacologic agents, isoform-selective pseudosubstrate peptides, and antisense oligonucleotides demonstrated that PKC(zeta) regulated local actin polymerization and bacterial engulfment, whereas other PKC isoforms did not. In contrast, opsonization of Hp with immunoglobulin G (IgG) induced rapid PKC(zeta)-independent uptake and enhanced killing of ingested bacteria. A role for atypical PKCs in phagocytosis has not been described. We conclude that Hp defines a new phagocytic pathway in macrophages that is regulated by PKC(zeta).
吞噬作用是巨噬细胞和中性粒细胞用来摄取和杀死微生物的一种快速的肌动蛋白依赖性内吞过程。吞噬作用的扰动是一些致病微生物致病能力的核心，我们之前证明，致溃疡细菌幽门螺杆菌（Hp）会积极延缓其被巨噬细胞摄取的过程，并随后在称为巨大体的新型液泡内存活。介导Hp结合的受体以及调节细菌吞噬的信号通路均未明确。然而，其他吞噬刺激并未表现出延迟吞噬作用这一事实表明，Hp可能通过一种独特的机制被摄取。我们现在表明，Hp在巨噬细胞中短暂激活蛋白激酶C（PKC），并且非典型PKCζ和新型PKCε，而非传统的PKCα，在形成的吞噬体上积累。药理学试剂、亚型选择性假底物肽和反义寡核苷酸表明，PKCζ调节局部肌动蛋白聚合和细菌吞噬，而其他PKC亚型则不然。相比之下，用免疫球蛋白G（IgG）对Hp进行调理会诱导快速的不依赖PKCζ的摄取，并增强对摄入细菌的杀伤作用。非典型PKC在吞噬作用中的作用尚未见报道。我们得出结论，Hp在巨噬细胞中定义了一条由PKCζ调节的新的吞噬途径。
