Underexpression of TIM-3 and Blunted Galectin-9-Induced Apoptosis of CD4+T Cells in Rheumatoid Arthritis
Underexpression of TIM-3 and Blunted Galectin-9-Induced Apoptosis of CD4+T Cells in Rheumatoid Arthritis
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DOI：
10.1007/s10753-011-9355-z
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发表时间：
2012-04-01
期刊：
影响因子：
5.1
通讯作者：
Cha, Hoon-Suk
中科院分区：
文献类型：
--
作者：
Lee, Jaejoon;Park, Eun-Jung;Cha, Hoon-Suk
本研究的目的是比较类风湿关节炎（RA）患者和健康对照者的CD 4 + T细胞中TIM-3的表达，并评估半乳糖凝集素-9（Galectin-9，Gal-9）对这些患者中CD 4 + T细胞凋亡的影响。从RA患者和健康对照的外周血单个核细胞中分离CD 4 + T细胞并活化。采用实时荧光定量PCR法检测CD 4 + T细胞中TIM-3 mRNA的表达。在梯度剂量的Gal-9或对照存在下活化CD 4 + T细胞，并且分别使用MTT测定和annexin-V染色分析Gal-9诱导的CD 4 + T细胞的细胞毒性和凋亡活性。与健康对照组相比，RA患者的CD 4 + T细胞中TIM-3 mRNA表达显著降低（p=0.028）。当与Gal-9（15 nM）孵育时，通过MTT测定测量的RA患者中的CD 4 + T细胞存活率显著高于健康对照（p=0.002）。如通过膜联蛋白染色测量的，来自健康对照的CD 4 + T细胞的凋亡活性随着Gal-9的分级剂量而增加（0 nM对30 nM，0 nM对90 nM，各自p=0.016）。然而，尽管用Gal-9刺激，但RA患者的CD 4 + T细胞的凋亡活性没有改变。Gal-9介导的CD 4 + T细胞凋亡在RA患者中功能失调。钝化Gal-9介导的细胞凋亡可能是通过负调节Th 1应答的TIM-3的低表达来实现的。我们的数据表明，TIM-3及其与Gal-9的相互作用可能在RA的发病机制中发挥重要作用，并可能代表一个潜在的治疗靶点。
The aim of this study is to compare the expression of TIM-3 from CD4+ T cells from rheumatoid arthritis (RA) patients and healthy controls and to evaluate the effect of galectin-9 (Gal-9) on apoptosis of CD4+ T cells in these patients. CD4+ T cells from RA patients and healthy controls were isolated from peripheral blood mononuclear cells and were activated. The expression of TIM-3 mRNA in CD4+ T cells was measured using real-time polymerase chain reaction. CD4+ T cells were activated in the presence of graded doses of Gal-9 or control, and Gal-9-induced cytotoxicity and apoptotic activity of CD4+ T cells were analyzed using MTT assays and annexin-V staining, respectively. TIM-3 mRNA expression was significantly lower in CD4+ T cells from RA patients compared with those in healthy controls (p=0.028). CD4+ T cell survival as measured by MTT assay when incubated with Gal-9 (15 nM) was significantly higher in RA patients than in healthy controls (p=0.002). Apoptotic activity of CD4+ T cells from healthy controls as measured by annexin staining increased with graded doses of Gal-9 (0 nM vs. 30 nM, 0 nM vs. 90 nM, p=0.016 each). However, apoptotic activity of CD4+ T cells from RA patients did not change despite the stimulation with Gal-9. Gal-9-mediated apoptosis of CD4+ T cells is dysfunctional in RA patients. Blunted Gal-9-mediated apoptosis may be exerted through underexpression of TIM-3 that negatively regulates Th1 response. Our data suggest that TIM-3 and its interaction with Gal-9 may play an important role in the pathogenesis of RA and may represent a potential therapeutic target.