Evidence for a functional role of the second C5a receptor C5L2
Evidence for a functional role of the second C5a receptor C5L2
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DOI：
10.1096/fj.04-3424fje
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发表时间：
2005-03-01
期刊：
影响因子：
4.8
通讯作者：
Ward, PA
中科院分区：
文献类型：
--
作者：
Gao, HW;Neff, TA;Ward, PA
在盲肠结扎和穿孔（CLP）后啮齿动物的实验性脓毒症期间，产生过量的C5 a，导致与C5 aR的相互作用、中性粒细胞的先天免疫功能的丧失和致死性。在目前的研究中，我们分析了第二个C5 a受体C5 L2的表达，C5 L2是C5 a的假定“默认”或非信号受体。克隆了大鼠C5 L2基因，并制备了C5 L2蛋白的抗体。CLP后，血液中性粒细胞显示C5 aR减少，随后恢复，而C5 L2水平逐渐增加，伴随着C5 L2 mRNA的出现。CLP期间肺和肝中C5 L2的mRNA增加。CLP后，肺、肝、心脏和肾中的C5 L2蛋白（通过I-125-抗C5 L2 IgG结合定义）显著增加。使用血清IL-6作为脓毒症的标志物，输注抗C5 aR显著降低血清IL-6水平，而与用正常IgG处理的CLP对照相比，抗C5 L2导致IL-6增加近4倍。当在体外用LPS和C5 a刺激正常血液中性粒细胞时，抗体对IL-6的释放具有相似的作用。这些数据提供了C5 L2在平衡对C5 a的生物反应中的作用的第一个证据。
During experimental sepsis in rodents after cecal ligation and puncture (CLP), excessive C5a is generated, leading to interactions with C5aR, loss of innate immune functions of neutrophils, and lethality. In the current study, we have analyzed the expression of the second C5a receptor C5L2, the putative "default" or nonsignaling receptor for C5a. Rat C5L2 was cloned, and antibody was developed to C5L2 protein. After CLP, blood neutrophils showed a reduction in C5aR followed by its restoration, while C5L2 levels gradually increased, accompanied by the appearance of mRNA for C5L2. mRNA for C5L2 increased in lung and liver during CLP. Substantially increased C5L2 protein (defined by binding of I-125-anti-C5L2 IgG) occurred in lung, liver, heart, and kidney after CLP. With the use of serum IL-6 as a marker for sepsis, infusion of anti-C5aR dramatically reduced serum IL-6 levels, while anti-C5L2 caused a nearly fourfold increase in IL-6 when compared with CLP controls treated with normal IgG. When normal blood neutrophils were stimulated in vitro with LPS and C5a, the antibodies had similar effects on release of IL-6. These data provide the first evidence for a role for C5L2 in balancing the biological responses to C5a.