Marleau S, Griffiths-Johnson D A, Collins P D, Bakhle Y S, Williams T J, Jose P J
National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, United Kingdom.
J Immunol. 1996 Nov 1;157(9):4141-6.
The guinea pig C-C chemokine, eotaxin, is a potent and selective eosinophil chemoattractant in guinea pig airways and skin in vivo, and stimulates both guinea pig and human eosinophils in vitro. The human C-C chemokine RANTES (30% homology with guinea pig eotaxin) stimulates human eosinophils in vitro, but does not stimulate guinea pig eosinophils, even though these cells bind 125I-RANTES. Similar concentrations of eotaxin and unlabeled RANTES competitively inhibit the binding of 125I-RANTES to guinea pig eosinophils, suggesting that eotaxin and RANTES share a common binding site on these cells. In the present study, we investigated the possibility that human RANTES, binding to a putative eotaxin receptor on guinea pig eosinophils, might block functional responses to eotaxin. When fura-2-loaded cells were first exposed to RANTES, which failed to elevate the intracellular calcium concentration, the response to a subsequent challenge with eotaxin was inhibited in a dose-dependent manner. Inhibition was also demonstrated when the two chemokines were added simultaneously. Another human C-C chemokine, MCP-3 (52% homology with guinea pig eotaxin), had similar inhibitory effects on the eotaxin-induced activation of guinea pig eosinophils in vitro. RANTES inhibited (111)In-eosinophil accumulation in response to intradermal eotaxin in vivo. In contrast, RANTES had no significant effect on responses to leukotriene B4 in vitro or in vivo. Thus, these experiments in the guinea pig demonstrate that human RANTES is the first prototypic antagonist of an eotaxin receptor.
豚鼠C-C趋化因子嗜酸性粒细胞趋化因子，在豚鼠气道和皮肤体内是一种强效且选择性的嗜酸性粒细胞趋化剂，在体外能刺激豚鼠和人类的嗜酸性粒细胞。人类C-C趋化因子RANTES（与豚鼠嗜酸性粒细胞趋化因子有30%的同源性）在体外能刺激人类嗜酸性粒细胞，但不能刺激豚鼠嗜酸性粒细胞，尽管这些细胞能结合125I-RANTES。相似浓度的嗜酸性粒细胞趋化因子和未标记的RANTES竞争性抑制125I-RANTES与豚鼠嗜酸性粒细胞的结合，这表明嗜酸性粒细胞趋化因子和RANTES在这些细胞上共享一个共同的结合位点。在本研究中，我们调查了人类RANTES结合豚鼠嗜酸性粒细胞上假定的嗜酸性粒细胞趋化因子受体，可能会阻断对嗜酸性粒细胞趋化因子的功能反应的可能性。当用fura-2加载的细胞首先暴露于未能提高细胞内钙浓度的RANTES时，对随后用嗜酸性粒细胞趋化因子进行刺激的反应以剂量依赖的方式受到抑制。当同时添加这两种趋化因子时也显示出抑制作用。另一种人类C-C趋化因子MCP-3（与豚鼠嗜酸性粒细胞趋化因子有52%的同源性），在体外对嗜酸性粒细胞趋化因子诱导的豚鼠嗜酸性粒细胞活化有类似的抑制作用。RANTES在体内抑制皮内注射嗜酸性粒细胞趋化因子后（111）In-嗜酸性粒细胞的聚集。相比之下，RANTES在体外或体内对白细胞三烯B4的反应没有显著影响。因此，这些在豚鼠身上进行的实验表明，人类RANTES是嗜酸性粒细胞趋化因子受体的首个原型拮抗剂。
