Division of Molecular Biology, [corrected] Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
Immunol Cell Biol. 2011 Mar;89(3):466-74. doi: 10.1038/icb.2010.108. Epub 2010 Sep 21.
Visceral leishmaniasis, which is caused by Leishmania donovani, is one of the major health problems of the Indian subcontinent. Infected hosts have been reported to have impaired lymphoproliferation. However, the fate of anergic cells is still elusive. In the present investigation, L. donovani-infected hamsters were used to study the mechanism of lymphocyte cell death. Lymph node-derived lymphocytes were analysed for apoptotic death through mitochondrial abnormality, caspase activity and DNA degradation. The data demonstrate that the disease progression leads to a gradual impairment of lymphocyte proliferation in the presence of Concanavalin A. The fate of the anergic lymphocytes is intrinsic apoptosis, which is evident by the depolarization of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and DNA fragmentation. Tumour growth factor (TGF)-β, which is secreted by macrophages, was significantly upregulated in the lymph node compartment of infected hamsters. Adding a neutralizing TGF-β antibody and a recombinant TGF-β resulted in the downregulation and induction of lymphocyte apoptosis, respectively. Furthermore, it has been observed that TGF-β triggers the apoptotic death of lymphocytes through the upregulation of tyrosine phosphatase activity and that the use of sodium orthovanadate (Na(3)VO(4), a tyrosine phosphatase inhibitor) reduces the apoptotic frequency. Thus, this study clearly reports the novel involvement of tyrosine phosphatases in TGF-β-induced lymphocyte apoptosis in Leishmania-infected hamsters.
内脏利什曼病是由利什曼原虫引起的，是印度次大陆的主要健康问题之一。据报道，受感染的宿主存在淋巴增殖受损的情况。然而，无能细胞的命运仍然难以捉摸。在本研究中，使用感染利什曼原虫的仓鼠来研究淋巴细胞死亡的机制。通过线粒体异常、半胱天冬酶活性和 DNA 降解，分析淋巴结来源的淋巴细胞的凋亡死亡。数据表明，疾病进展导致在伴刀豆球蛋白 A 存在的情况下，淋巴细胞增殖逐渐受损。无能淋巴细胞的命运是内在凋亡，这可以通过线粒体膜电位去极化、细胞色素 c 胞质释放、半胱天冬酶激活和 DNA 片段化来证明。肿瘤生长因子 (TGF)-β 由巨噬细胞分泌，在感染仓鼠的淋巴结区室中显著上调。添加中和 TGF-β 抗体和重组 TGF-β 分别导致淋巴细胞凋亡的下调和诱导。此外，已经观察到 TGF-β 通过上调酪氨酸磷酸酶活性触发淋巴细胞的凋亡死亡，并且使用偏钒酸钠 (Na(3)VO(4)，一种酪氨酸磷酸酶抑制剂) 降低凋亡频率。因此，本研究清楚地报告了酪氨酸磷酸酶在 TGF-β 诱导的利什曼原虫感染仓鼠淋巴细胞凋亡中的新作用。
