Aoki K, Kurooka M, Chen J J, Petryniak J, Nabel E G, Nabel G J
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892-3005, USA.
Nat Immunol. 2001 Apr;2(4):333-7. doi: 10.1038/86336.
Fas ligand (CD95L) is synthesized both on the cell surface membrane and in a soluble form. Although CD95L contributes to immune privilege in the cornea and testis, the functions of these alternatively processed proteins are not well understood. Some reports suggest that the cytotoxicity of soluble CD95L is insignificant, whereas others show potent responses in vivo, including hepatocyte apoptosis that causes liver failure. We show here that extracellular matrix proteins interact with soluble CD95L and potentiate its pro-apoptotic activity. The cytotoxicity of supernatants from CD95L-expressing cells was increased by incubation on tissue culture plates coated with these matrix proteins; this effect was mediated by trimeric soluble CD95L. With the use of immunoprecipitation, it was found that CD95L binds directly to fibronectin. In addition, immunohistochemical analysis of the cornea revealed that soluble CD95L binds primarily to extracellular matrix. The retention of soluble CD95L on extracellular matrices is likely to play an important role in the development of peripheral tolerance in immune-privileged sites.
Fas配体（CD95L）可在细胞表面膜上以及以可溶性形式合成。尽管CD95L有助于角膜和睾丸的免疫赦免，但这些经过不同加工的蛋白质的功能尚未完全明确。一些报告表明可溶性CD95L的细胞毒性不显著，而另一些报告则显示其在体内有强烈反应，包括导致肝衰竭的肝细胞凋亡。我们在此表明，细胞外基质蛋白与可溶性CD95L相互作用并增强其促凋亡活性。在涂有这些基质蛋白的组织培养板上孵育后，表达CD95L的细胞上清液的细胞毒性增加；这种效应由三聚体可溶性CD95L介导。通过免疫沉淀发现，CD95L直接与纤连蛋白结合。此外，角膜的免疫组织化学分析显示，可溶性CD95L主要与细胞外基质结合。可溶性CD95L在细胞外基质上的保留可能在免疫赦免部位外周耐受的发展中起重要作用。
