Convergence of Fcγ receptor IIA and Fcγ receptor IIIB signaling pathways in human neutrophils
Convergence of Fcγ receptor IIA and Fcγ receptor IIIB signaling pathways in human neutrophils
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DOI：
10.4049/jimmunol.164.1.350
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发表时间：
2000-01-01
影响因子：
4.4
通讯作者：
Unkeless, JC
中科院分区：
文献类型：
--
作者：
Chuang, FYS;Sassaroli, M;Unkeless, JC
人中性粒细胞（PMN）表达IgG Fc结构域的两种受体：跨膜Fc γ RIIA（其胞质序列含有基于免疫受体酪氨酸的活化基序）和GPI锚定的Fc γ RIIIB。Fc γ RIIIB的交联诱导细胞活化，但其机制仍不确定。我们已经使用单克隆抗体选择性地交联这两种受体中的每一种，并评估它们的信号传导表型和功能关系。Fc γ RIIIB的交联诱导细胞内Ca 2+释放和受体加帽。钙响应被阻断渥曼青霉素和N，N-二甲基鞘氨醇，抑制剂磷脂酰肌醇3-激酶和鞘氨醇激酶，分别。对于通过交联Fc γ RIIA刺激的Ca 2+释放，获得了相同的剂量-反应曲线，表明这两种酶存在共同的信号传导途径。渥曼青霉素还抑制两种受体的加帽作用，但不抑制受体内吞作用。双标记的PMN中的荧光显微镜检查证实Fc γ RIIA与交联的Fc γ RIIIB共定位。两种受体的信号传导表型仅在吞噬作用受阻的条件下不同，其中与底物固定化Ab结合的Fc γ RIIIB不引起细胞扩散。我们提出Fc γ RIIIB信号传导由Fc γ RIIA分子进行，所述分子被募集到由成簇的Fc γ RIIIB诱导的蛋白质/脂质结构域，因此，被并置用于基于免疫受体酪氨酸的活化蛾磷酸化和PMN活化。
Human neutrophils (PMNs) express two receptors for the Fc domain of IgG: the transmembrane Fc gamma RIIA, whose cytosolic sequence contains an immunoreceptor tyrosine-based activation motif, and the GPI-anchored Fc gamma RIIIB. Cross-Linking of Fc gamma RIIIB induces cell activation, but the mechanism is still uncertain. We have used mAbs to cross-link selectively each of the two receptors and to assess their signaling phenotypes and functional relation. Cross-linking of Fc gamma RIIIB induces intracellular Ca2+ release and receptor capping. The Ca2+ response is blocked by wortmannin and by N,N-dimethylsphingosine, inhibitors of phosphatidylinositol 3-kinase and sphingosine kinase, respectively. Identical dose-response curves are obtained for the Ca2+ release stimulated by cross-linking Fc gamma RIIA, implicating these two enzymes in a common signaling pathway. Wortmannin also inhibits capping of both receptors, but not receptor endocytosis. Fluorescence microscopy in double-labeled PMNs demonstrates that Fc gamma RIIA colocalizes with cross-linked Fc gamma RIIIB. The signaling phenotypes of the two receptors diverge only under frustrated phagocytosis conditions, where Fc gamma RIIIB bound to substrate-immobilized Ab does not elicit cell spreading. We propose that Fc gamma RIIIB signaling is conducted by molecules of Fc gamma RIIA that are recruited to protein/lipid domains induced by clustered Fc gamma RIIIB and, thus, are brought into juxtaposition for immunoreceptor tyrosine-based activation moth phosphorylation and activation of PMNs.