Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors

作     者：Proudfoot, AEI Buser, R Borlat, F Alouani, S Soler, D Offord, RE Schröder, JM Power, CA Wells, TNC 

作者机构：Serono Pharmaceut Res Inst Geneva Switzerland LeukoSite Inc Cambridge MA 02142 USA Univ Kiel Dept Dermatol & Allergol Kiel Germany Ctr Med Univ Geneva Dept Biochim Med CH-1228 Geneva Switzerland 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：1999年第274卷第45期

页      面：32478-32485页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

主　　题：抗HIV药/药理学 结合 竞争性 趋化因子CCL5/类似物和衍生物 趋化因子CCL5/药理学 趋化作用/药物作用 仓鼠亚科 减量调节 HIV-1/致病力 单核细胞/药物作用 单核细胞/代谢 受体 CCR1 受体 CCR3 受体 CCR5/代谢 受体 趋化因子/药物作用 受体 趋化因子/代谢 表面特性 动物 

摘      要：Modification of the amino terminus of regulated on activated normal T-cell expressed (RANTES) has been shown to have a significant effect on biological activity and produces proteins with antagonist properties. Two amino-terminally modified RANTES proteins, Met-RANTES and aminooxypentane-RANTES (AOP-RANTES), exhibit differential inhibitory properties on both monocyte and eosinophil chemotaxis, We have investigated their binding properties as well as their ability to activate the RANTES receptors CCR1, CCR3, and CCR5 in cell lines overexpressing these receptors, We show that Met-RANTES has weak activity in eliciting a calcium response in Chinese hamster ovary cells expressing CCR1, CCR3, and CCR5, whereas AOP-RANTES has full agonist activity on CCR5 but is less effective on CCR3 and CCR1, Their ability to induce chemotaxis of the murine pre-B lymphoma cell line, L1.2, transfected with the same receptors, consolidates these results, Monocytes have detectable mRNA for CCR1, CCR2, CCR3, CCR4, and CCR5, and they respond to the ligands for these receptors in chemotaxis but not always in calcium mobilization, AOP-RANTES does not induce calcium mobilization in circulating monocytes but is able to do so as these cells acquire the macrophage phenotype, which coincides with a concomitant up-regulation of CCR5, We have also tested the ability of both modified proteins to induce chemotaxis of freshly isolated monocytes and eosinophils, Cells from most donors do not respond, but occasionally cells from a particular donor do respond, particularly to AOP-RANTES, We therefore hypothesize that the occasional activity of AOP-RANTES to induce leukocyte chemotaxis is due to donor to donor variation of receptor expression.