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Abstract：
CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)-based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.
摘要：
CXCL17是一种主要由粘膜组织表达的趋化因子，它促进单核细胞的趋化性，树突状细胞,和巨噬细胞，并具有抗菌特性。CXCL17还与炎症性疾病的病理学和几种癌症的进展有关。其表达在肺部病毒感染期间增加。然而,CXCL17在健康和疾病中的确切作用需要进一步研究，并且需要确认介导CXCL17功能反应的分子靶标。使用一系列基于生物发光共振能量转移（BRET）的测定，我们证明CXCL17抑制CXCR4介导的信号传导和配体结合.此外，CXCL17与VEGFR2共受体神经柱蛋白-1相互作用。此外,我们发现CXCL17仅抑制完整细胞中的CXCR4配体结合，并证明这种作用被已知的糖胺聚糖结合剂模拟，Surfen和硫酸鱼精蛋白.CXCL17中推定的GAG结合结构域的破坏阻止了CXCR4的结合。这表明CXCL17通过可能需要存在含糖胺聚糖的辅助蛋白的作用机制抑制CXCR4。一起,我们的结果显示,CXCL17是CXCR4的内源性抑制剂,代表了我们对CXCL17功能和CXCR4信号调节的理解的下一步.
