Ogawa Noriyoshi, Shimoyama Kumiko, Kawanami Takafumi
Department of Hematology and Immunology, Kanazawa Medical University, Japan.
Nihon Rinsho Meneki Gakkai Kaishi. 2005 Feb;28(1):10-20. doi: 10.2177/jsci.28.10.
IFNgamma plays an important role to induce several functional molecules on salivary epithelial cells, including class II MHC, Fas and CD40 in salivary glands from patients with Sjogren's syndrome (SS). IFNgamma also contributes to the development of lymphocytic infiltrates by inducing T cell attracting chemokines in SS salivary epithelial cells, such as IP-10 (CXCL10), Mig (CXCL9), and I-TAC (CXCL11). IFNgamma dysregulation in SS salivary gland may attribute to the decreased production of TGFbeta from salivary epithelial cells in some patients. Expression of Fas and CD40 was significantly higher in SS salivary epithelial cells than in normal cells after IFNgamma stimulation. Although neither anti-Fas (CH11) nor anti-CD40 mAb alone could induce typical apoptosis, the two together and preincubation with IFNgamma efficiently induced apoptosis in SS salivary epithelial cells. This apoptosis was almost completely blocked by neutralizing anti-Fas mAb (ZB4). c-FLIP, an important inhibitory molecule in the Fas death pathway, was strongly expressed in SS salivary epithelial cells, but its expression was downregulated, at the protein level, by anti-CD40 mAb. CD40 signals promote Fas-dependent death of SS salivary epithelial cells by downregulating c-FLIP expression. The presence of c-FLIP in these cells may explain their resistance to undergo apoptosis in response to either anti-Fas or anti-CD40 mAb, despite their surface expression of both proteins. These findings suggest that SS salivary epithelial cell death requires the cooperation of Fas and CD40.
干扰素γ在诱导干燥综合征（SS）患者唾液腺的唾液上皮细胞上的多种功能分子方面发挥重要作用，这些分子包括II类主要组织相容性复合体、Fas和CD40。干扰素γ还通过在SS唾液上皮细胞中诱导吸引T细胞的趋化因子，如IP-10（CXCL10）、Mig（CXCL9）和I-TAC（CXCL11），促进淋巴细胞浸润的发展。SS唾液腺中干扰素γ的失调可能归因于一些患者唾液上皮细胞中转化生长因子β的产生减少。在干扰素γ刺激后，SS唾液上皮细胞中Fas和CD40的表达明显高于正常细胞。尽管单独的抗Fas（CH11）或抗CD40单克隆抗体都不能诱导典型的凋亡，但两者一起并与干扰素γ预孵育能有效地诱导SS唾液上皮细胞凋亡。这种凋亡几乎完全被中和性抗Fas单克隆抗体（ZB4）阻断。c-FLIP是Fas死亡途径中的一种重要抑制分子，在SS唾液上皮细胞中强烈表达，但其表达在蛋白水平上被抗CD40单克隆抗体下调。CD40信号通过下调c-FLIP表达促进SS唾液上皮细胞的Fas依赖性死亡。这些细胞中c-FLIP的存在可能解释了尽管它们表面同时表达这两种蛋白，但它们对单独的抗Fas或抗CD40单克隆抗体诱导的凋亡具有抗性。这些发现表明，SS唾液上皮细胞死亡需要Fas和CD40的协同作用。
