The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions.
The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions.
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DOI：
10.1074/jbc.m116.720953
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发表时间：
2016-06-10
期刊：
影响因子：
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通讯作者：
Handel TM
中科院分区：
文献类型：
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作者：
Dyer DP;Salanga CL;Johns SC;Valdambrini E;Fuster MM;Milner CM;Day AJ;Handel TM
肿瘤坏死因子刺激基因-6（TSG-6）是一种多功能蛋白质，由多种细胞（包括中性粒细胞、单核细胞和内皮细胞）响应促炎刺激而分泌。在疾病模型中给药时，已显示其部分通过减少中性粒细胞浸润介导抗炎和保护作用。人TSG-6通过其连接模块（Link_TSG 6）结合CXCL 8并干扰CXCL 8在细胞表面糖胺聚糖（GAG）上的呈递（一种对许多趋化因子功能至关重要的相互作用）来抑制中性粒细胞迁移。还发现TSG-6与趋化因子CXCL 11和CCL 5相互作用，这表明它可能作为一种广泛特异性的趋化因子结合蛋白发挥作用，其功能与病毒编码的趋化因子结合蛋白相似。因此，本研究旨在探索TSG-6调节其他趋化因子功能的能力。在此，我们证明Link_TSG6结合来自CXC和CC家族的趋化因子，包括CXCL 4、CXCL 12、CCL 2、CCL 5、CCL 7、CCL 19、CCL 21和CCL 27。我们还表明，Link_TSG6的结合位点的趋化因子重叠与趋化因子GAG结合位点，这些趋化因子的亲和力Link_TSG6（KD值1-85 nm）广泛相关的趋化因子GAG的亲和力。Link_TSG6还不仅通过与趋化因子的直接相互作用，而且通过结合并因此掩蔽GAG的可用性来抑制趋化因子在内皮细胞上的呈递。沿着先前的工作，这些发现表明TSG-6通过调节趋化因子/GAG相互作用而作为趋化因子的多能调节剂起作用，这可能是TSG-6在体内产生其抗炎作用的主要机制。
TNF-stimulated gene-6 (TSG-6) is a multifunctional protein secreted in response to pro-inflammatory stimuli by a wide range of cells, including neutrophils, monocytes, and endothelial cells. It has been shown to mediate anti-inflammatory and protective effects when administered in disease models, in part, by reducing neutrophil infiltration. Human TSG-6 inhibits neutrophil migration by binding CXCL8 through its Link module (Link_TSG6) and interfering with the presentation of CXCL8 on cell-surface glycosaminoglycans (GAGs), an interaction that is vital for the function of many chemokines. TSG-6 was also found to interact with chemokines CXCL11 and CCL5, suggesting the possibility that it may function as a broad specificity chemokine-binding protein, functionally similar to those encoded by viruses. This study was therefore undertaken to explore the ability of TSG-6 to regulate the function of other chemokines. Herein, we demonstrate that Link_TSG6 binds chemokines from both the CXC and CC families, including CXCL4, CXCL12, CCL2, CCL5, CCL7, CCL19, CCL21, and CCL27. We also show that the Link_TSG6-binding sites on chemokines overlap with chemokine GAG-binding sites, and that the affinities of Link_TSG6 for these chemokines (KD values 1–85 nm) broadly correlate with chemokine-GAG affinities. Link_TSG6 also inhibits chemokine presentation on endothelial cells not only through a direct interaction with chemokines but also by binding and therefore masking the availability of GAGs. Along with previous work, these findings suggest that TSG-6 functions as a pluripotent regulator of chemokines by modulating chemokine/GAG interactions, which may be a major mechanism by which TSG-6 produces its anti-inflammatory effects in vivo.