Transmembrane TNF-α promotes activation-induced cell death by forward and reverse signaling.
Transmembrane TNF-α promotes activation-induced cell death by forward and reverse signaling.
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跨膜 TNF-α 通过正向和反向信号传导促进激活诱导的细胞死亡
DOI：
10.18632/oncotarget.19124
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发表时间：
2017-09-08
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Zhang M;Wang J;Jia L;Huang J;He C;Hu F;Yuan L;Wang G;Yu M;Li Z
分泌性肿瘤坏死因子-α (sTNF-α)介导活化诱导的细胞死亡（AICD）。然而，tmTNF-α在AICD中的作用尚不清楚。本研究表明，Jurkat和人原代T细胞在AICD期间，tmTNF-α表达显著增加，同时细胞凋亡增加。激活T细胞中tmTNF-α表达的下调或增强分别抑制或促进AICD。用外源性tmTNF-α处理活化的T细胞可显著增强AICD，表明tmTNF-α作为效应分子介导AICD。由于tmTNF-α可以作为受体发挥作用，因此使用抗tnf -α多克隆抗体触发tmTNF-α的反向信号传导。该抗体处理上调Fas配体、TNF相关凋亡诱导配体和tmTNF-α的表达，扩增AICD，促进表达死亡受体4、TNF受体（TNFR） 1和TNFR2的活化T细胞，增强其对AICD的敏感性。敲低TNFR1或TNFR2表达完全阻断tmTNF-α反向信号，分别增加对sTNF-α或tmTNF-α介导的AICD的敏感性。我们的研究结果表明，tmTNF-α在AICD介导中作为死亡配体发挥作用，并在活化T细胞对AICD的敏化中作为受体发挥作用。靶向活化T细胞中的tmTNF-α可能有助于促进AICD治疗自身免疫性疾病。
Secretory tumor necrosis factor-alpha (sTNF-α) is known to mediate activation- induced cell death (AICD). However, the role of tmTNF-α in AICD is still obscure. Here, we demonstrated that tmTNF-α expression significantly increased accompanied with enhanced apoptosis during AICD in Jurkat and primary human T cells. Knockdown or enhancement of tmTNF-α expression in activated T cells suppressed or promoted AICD, respectively. Treatment of activated T cells with exogenous tmTNF-α significantly augmented AICD, indicating that tmTNF-α as an effector molecule mediates AICD. As tmTNF-α can function as a receptor, an anti-TNF-α polyclonal antibody was used to trigger reverse signaling of tmTNF-α. This antibody treatment upregulated the expression of Fas ligand, TNF-related apoptosis-inducing ligand and tmTNF-α to amplify AICD, and promoted activated T cells expressing death receptor 4, TNF receptor (TNFR) 1 and TNFR2 to enhance their sensitivity to AICD. Knockdown of TNFR1 or TNFR2 expression totally blocked tmTNF-α reverse signaling increased sensitivity to sTNF-α- or tmTNF-α-mediated AICD, respectively. Our results indicate that tmTNF-α functions as a death ligand in mediation of AICD and as a receptor in sensitization of activated T cells to AICD. Targeting tmTNF-α in activated T cells may be helpful in facilitating AICD for treatment of autoimmune diseases.
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影响因子：
4.4
作者：
Xiao, S;Deshmukh, US;Ju, ST
通讯作者：
Ju, ST
影响因子：
1.3
作者：
Arakaki, Rieko;Yamada, Akiko;Ishimaru, Naozumi
通讯作者：
Ishimaru, Naozumi
DOI：
10.1006/clin.1996.4291
发表时间：
1997-02-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
Higuchi, M;Nagasawa, K;Niho, Y
通讯作者：
Niho, Y
影响因子：
5.4
作者：
Speiser, DE;Sebzda, E;Ohashi, PS
通讯作者：
Ohashi, PS
影响因子：
32.4
作者：
Sytwu, HK;Liblau, RS;McDevitt, HO
通讯作者：
McDevitt, HO