Induction of TRAIL- and TNF-α-Dependent Apoptosis in Human Monocyte-Derived Dendritic Cells by Microfilariae of Brugia malayi
Induction of TRAIL- and TNF-α-Dependent Apoptosis in Human Monocyte-Derived Dendritic Cells by Microfilariae of Brugia malayi
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DOI：
10.4049/jimmunol.181.10.7081
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发表时间：
2008-11-15
影响因子：
4.4
通讯作者：
Nutman, Thomas B.
中科院分区：
文献类型：
--
作者：
Semnani, Roshanak Tolouei;Venugopal, Priyanka Goel;Nutman, Thomas B.
专职APC的失调被认为是未闭丝虫感染患者Ag特异性T细胞低反应性的主要机制。为了解决这种失调的性质，树突状细胞（DC）和巨噬细胞从淘洗的单核细胞产生暴露于活微丝蚴（MF），寄生虫阶段，在血液中循环，并负责大多数免疫失调丝虫感染。与未暴露的DC相比，暴露于MF 24-96 h的DC显示细胞死亡和半胱天冬酶阳性细胞显著增加，而MF暴露不诱导巨噬细胞凋亡。有趣的是，48小时暴露的DC MF诱导的促凋亡基因TRAIL的mRNA表达和TNF-α的mRNA和蛋白质表达。TRAIL-R2、TNF-R1或TNF-alpha的mAb部分逆转了MF诱导的DC细胞死亡，正如使用小干扰RNA敲低TRAIL-R2受体一样。MF还诱导DC中BH 3相互作用结构域死亡激动剂的基因表达和细胞色素c的蛋白表达; MF诱导的BH 3相互作用结构域死亡激动剂的裂解可显示诱导细胞色素c的释放，导致半胱天冬酶9的激活。我们的数据表明，MF诱导DC凋亡的TRAIL和TNF-α依赖的方式。免疫学杂志，2008，181：7081-7089.
Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24-96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, whereas mf exposure did not induce apoptosis in macrophages. Interestingly, 48-h exposure of DC to mf induced mRNA expression of the proapoptotic gene TRAIL and both mRNA and protein expression of TNF-alpha. mAb to TRAIL-R2, TNF-R1, or TNF-alpha partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. The mf also induced gene expression of BH3-interacting domain death agonist and protein expression of cytochrome c in DC; mf-induced cleavage of BH3-interacting domain death agonist could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-alpha-dependent fashion. The Journal of Immunology, 2008, 181: 7081-7089.