Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL
Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL
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DOI：
10.4049/jimmunol.1101610
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发表时间：
2012-05-15
影响因子：
4.4
通讯作者：
Holter, Wolfgang
中科院分区：
文献类型：
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作者：
Lehner, Manfred;Kellert, Beate;Holter, Wolfgang
树突状细胞（DCs）的寿命是由促凋亡和抗凋亡蛋白的平衡决定的。在本研究中，我们报道了用多肌苷酸-多胞酸或LPS刺激TLR后无血清培养的人单核细胞来源的dc发生凋亡，这与低TNF的产生有关。添加外源性TNF或同时刺激R-848可阻止细胞凋亡，R-848可强烈放大内源性TNF的产生。TNF的中和证实DC存活是由R-848刺激或CD40结扎诱导的自分泌TNF介导的。另一种已知的DC凋亡诱导剂多肌苷酸-多胞苷酸或ifn - β刺激DC，其特征是高水平和激活促凋亡蛋白BAK。抗凋亡BCL-2与BAK的比值与活化的dc的存活最相关。TNF的加入增加了这一比例，但对BAX和MAP的影响不大。使用小干扰rna的敲低实验证实，激活的和未成熟的dc的存活受到BAK的调节，并表明TNF仅在FLIPL存在时才具有保护作用。总之，我们的数据表明，dc在分化和激活过程中的存活取决于自分泌TNF，而BAK的抑制在这一过程中起着重要作用。中华免疫学杂志，2012,18(8):1010 - 1018。
The life span of dendritic cells (DCs) is determined by the balance of pro- and antiapoptotic proteins. In this study, we report that serum-free cultured human monocyte-derived DCs after TLR stimulation with polyinosinic acid-polycytidylic acid or LPS underwent apoptosis, which was correlated with low TNF production. Apoptosis was prevented by the addition of exogenous TNF or by concomitant stimulation with R-848, which strongly amplified endogenous TNF production. Neutralization of TNF confirmed that DC survival was mediated by autocrine TNF induced either by stimulation with R-848 or by ligation of CD40. DCs stimulated by polyinosinic acid-polycytidylic acid or IFN-beta, another known inducer of DC apoptosis, were characterized by high levels and activation of the proapoptotic protein BAK. The ratio of antiapoptotic BCL-2 to BAK correlated best with the survival of activated DCs. Addition of TNF increased this ratio but had little effect on BAX and MAP. Knockdown experiments using small interfering RNAs confirmed that the survival of activated and also of immature DCs was regulated by BAK and showed that TNF was protective only in the presence of FLIPL. Together, our data demonstrate that the survival of DCs during differentiation and activation depends on autocrine TNF and that the inhibition of BAK plays an important role in this process. The Journal of Immunology, 2012, 188: 4810-4818.