The transmembrane CXC-chemokine ligand 16 is induced by IFN-γ and TNF-α and shed by the activity of the disintegrin-like metalloproteinase ADAM10
The transmembrane CXC-chemokine ligand 16 is induced by IFN-γ and TNF-α and shed by the activity of the disintegrin-like metalloproteinase ADAM10
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DOI：
10.4049/jimmunol.172.10.6362
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发表时间：
2004-05-15
影响因子：
4.4
通讯作者：
Ludwig, A
中科院分区：
文献类型：
--
作者：
Abel, S;Hundhausen, C;Ludwig, A
新型CXC趋化因子配体16（CXCL 16）作为APC表面的跨膜粘附分子和作为活化的T细胞的可溶性化学引诱物发挥功能。在这项研究中，我们阐明了跨膜分子转化为可溶性趋化因子的机制，并为成纤维细胞和血管细胞表达和脱落CXCL 16提供证据。通过在不同细胞系中转染人和鼠CXCL 16，我们表明可溶性CXCL 16是由跨膜CXCL 16的蛋白水解切割组成性产生的，从而导致跨膜分子的表面表达减少。用选择性异羟肟酸抑制剂对去整合素样金属蛋白酶a去整合素和金属蛋白酶结构域（ADAM）10和ADAM 17的抑制实验表明，ADAM 10而不是ADAM 17参与组成性CXCL 16裂解。此外，转染的人CXCL 16的组成型裂解显着减少从ADAM 10缺陷小鼠产生的胚胎成纤维细胞。通过用IFN-γ和TNF-α诱导ADAM 10缺陷成纤维细胞中的小鼠CXCL 16，我们表明内源性ADAM 10确实参与内源性CXCL 16的释放。最后，内源性CXCL 16的脱落可以通过用ADAM 10再转染ADAM 10缺陷细胞来重建。通过分析培养的血管细胞CXCXL 16的表达和释放，我们发现IFN-γ和TNF-α协同诱导CXCL 16 mRNA。CXCL 16从内皮细胞表面的组成性脱落被ADAM 10的抑制剂阻断，并且不依赖于ADAM 17的额外抑制。因此，在脉管系统中的炎症期间，ADAM 10可以充当CXCL 16脱落酶，从而精细地控制炎症组织中CXCL 16的表达和功能。
The novel CXC-chemokine ligand 16 (CXCL16) functions as transmembrane adhesion molecule on the surface of APCs and as a soluble chemoattractant for activated T cells. In this study, we elucidate the mechanism responsible for the conversion of the transmembrane molecule into a soluble chemokine and provide evidence for the expression and shedding of CXCL16 by fibroblasts and vascular cells. By transfection of human and murine CXCL16 in different cell lines, we show that soluble CXCL16 is constitutively generated by proteolytic cleavage of transmembrane CXCL16 resulting in reduced surface expression of the transmembrane molecule. Inhibition experiments with selective hydroxamate inhibitors against the disintegrin-like metalloproteinases a disintegrin and metalloproteinase domain (ADAM)10 and ADAM17 suggest that ADAM10, but not ADAM17, is involved in constitutive CXCL16 cleavage. In addition, the constitutive cleavage of transfected human CXCL16 was markedly reduced in embryonic fibroblasts generated from ADAM10-deficient mice. By induction of murine CXCL16 in ADAM10-deficient fibroblasts with IFN-gamma and TNF-alpha, we show that endogenous ADAM10 is indeed involved in the release of endogenous CXCL16. Finally, the shedding of endogenous CXCL16 could be reconstituted by retransfection of ADAM10-deficient cells with ADAM10. Analyzing the expression and release of CXCXL16 by cultured vascular cells, we found that IFN-gamma and TNF-alpha synergize to induce CXCL16 mRNA. The constitutive shedding of CXCL16 from the endothelial cell surface is blocked by inhibitors of ADAM10 and is independent of additional inhibition of ADAM17. Hence, during inflammation in the vasculature, ADAM10 may act as a CXCL16 sheddase and thereby finely control the expression and function of CXCL16 in the inflamed tissue.