Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
Merck Research Laboratories, Molecular Pharmacology & DMPK, Oss, The Netherlands.
J Immunol. 2014 Apr 15;192(8):3908-3914. doi: 10.4049/jimmunol.1302159. Epub 2014 Mar 17.
Chemokines comprise a family of secreted proteins that activate G protein-coupled chemokine receptors and thereby control the migration of leukocytes during inflammation or immune surveillance. The positional information required for such migratory behavior is governed by the binding of chemokines to membrane-tethered glycosaminoglycans (GAGs), which establishes a chemokine concentration gradient. An often observed but incompletely understood behavior of chemokines is the ability of unrelated chemokines to enhance the potency with which another chemokine subtype can activate its cognate receptor. This phenomenon has been demonstrated to occur between many chemokine combinations and across several model systems and has been dubbed chemokine cooperativity. In this study, we have used GAG binding-deficient chemokine mutants and cell-based functional (migration) assays to demonstrate that chemokine cooperativity is caused by competitive binding of chemokines to GAGs. This mechanistic explanation of chemokine cooperativity provides insight into chemokine gradient formation in the context of inflammation, in which multiple chemokines are secreted simultaneously.
趋化因子是一组分泌蛋白，能够激活 G 蛋白偶联趋化因子受体，从而控制白细胞在炎症或免疫监视过程中的迁移。这种迁移行为所需的位置信息受趋化因子与膜结合糖胺聚糖（GAGs）的结合控制，从而建立趋化因子浓度梯度。趋化因子的一个常见但不完全理解的行为是，不相关的趋化因子能够增强另一种趋化因子亚型激活其同源受体的效力。这种现象已经在许多趋化因子组合和几个模型系统中得到证实，并被称为趋化因子协同作用。在这项研究中，我们使用 GAG 结合缺陷型趋化因子突变体和基于细胞的功能（迁移）测定法证明，趋化因子协同作用是由趋化因子与 GAGs 的竞争性结合引起的。这种趋化因子协同作用的机制解释提供了对炎症中趋化因子梯度形成的深入了解，在炎症中，多种趋化因子同时被分泌。
