Differential signaling of formyl peptide receptor-like 1 by Trp-Lys-Tyr-Met-Val-Met-CONH2 or lipoxin A4 in human neutrophils
Differential signaling of formyl peptide receptor-like 1 by Trp-Lys-Tyr-Met-Val-Met-CONH2 or lipoxin A4 in human neutrophils
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DOI：
10.1124/mol.64.3.721
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发表时间：
2003-09-01
影响因子：
3.6
通讯作者：
Ryu, SH
中科院分区：
文献类型：
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作者：
Bae, YS;Park, JC;Ryu, SH
经典的化学引诱物受体对免疫应答具有根本的重要性。这类受体的两个主要作用是调节趋化性和产生活性氧。甲酰肽受体样1（FPRL 1）可被两种不同的配体Trp-Lys-Tyr-Met- Val-Met-CONH 2（WKYMVM）和脂氧素A4（LXA 4）刺激。虽然已经报道了由激活的FPRL 1介导的白细胞趋化性，但FPRL 1在超氧化物生成中的作用仍有待研究。在这项研究中，我们研究了WKYMVM或LXA 4对人中性粒细胞趋化性迁移和超氧化物生成的影响。WKYMVM和LXA 4通过酪氨酸磷酸化事件刺激中性粒细胞趋化性。在活性氧产生方面，WKYMVM而不是LXA 4刺激中性粒细胞中超氧化物的产生。为了理解通过相同受体FPRL 1产生超氧化物的这种差异，我们比较了两种不同配体在FPRL 1下游的信号通路。首先，我们证实WKYMVM和LXA 4均以百日咳毒素敏感的方式引起细胞内钙（[Ca 2 +]（i））增加，并且这些配体在中性粒细胞中竞争性抑制（[Ca 2 +]（i））增加。这一结果表明，WKYMVM和LXA 4共享相同的受体FPRL 1。通过研究WKYMVM和LXA 4的细胞信号传导，我们发现WKYMVM而不是LXA 4诱导细胞外信号调节蛋白激酶（ERK）、c-Jun NH 2-末端激酶和磷脂酶A（2）（PLA（2））活化。我们还发现ERK介导的胞质PLA（2）活性对超氧化物的产生是必不可少的。这些结果表明，两种不同配体对FPRL 1的激活可诱导人中性粒细胞中的差异细胞信号传导和独特的功能后果。
Classical chemoattractant receptors are of fundamental importance to immune responses. The two major roles of such receptors are the modulation of chemotaxis and the generation of reactive oxygen species. The formyl peptide receptor-like 1 (FPRL1) can be stimulated by two different ligands, Trp-Lys-Tyr-Met- Val-Met-CONH2 ( WKYMVM) and lipoxin A4 (LXA4). Although leukocyte chemotaxis mediated by activated FPRL1 has been reported, the role of FPRL1 in superoxide generation remains to be studied. In this study, we examined the effect of WKYMVM or LXA4 on chemotactic migration and superoxide generation in human neutrophils. WKYMVM and LXA4 stimulated neutrophil chemotaxis via tyrosine phosphorylation events. In terms of reactive oxygen species generation, WKYMVM but not LXA4 stimulated superoxide generation in neutrophils. To understand this difference on superoxide generation via the same receptor, FPRL1, we compared the signaling pathways downstream of FPRL1 by the two different ligands. At first, we confirmed that both WKYMVM and LXA4 caused intracellular calcium ([Ca2+](i)) increase in a pertussis toxin-sensitive manner and that these ligands competitively inhibited each other with respect to ([Ca2+](i)) increase in neutrophils. This result suggests that WKYMVM and LXA4 share the same receptor, FPRL1. By investigating cellular signaling by WKYMVM and LXA4, we found that WKYMVM but not LXA4 induced extracellular signal-regulated protein kinases ( ERKs), c-Jun NH2-terminal kinase, and phospholipase A(2) (PLA(2)) activation. We also found that ERK-mediated cytosolic PLA(2) activity is essential for superoxide generation. These results indicate that the activation of FPRL1 by the two different ligands can induce differential cellular signaling and unique functional consequences in human neutrophils.