Crosstalk between RANKL and Fas signaling in dendritic cells controls immune tolerance
Crosstalk between RANKL and Fas signaling in dendritic cells controls immune tolerance
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DOI：
10.1182/blood-2006-11-059980
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发表时间：
2007-07-01
期刊：
影响因子：
20.3
通讯作者：
Hayashi, Yoshio
中科院分区：
文献类型：
--
作者：
Izawa, Takashi;Ishimaru, Naozurni;Hayashi, Yoshio
尽管核因子受体活化因子（NF）-κ B配体（RANKL）信号通路已被证明可延长成熟树突状细胞（DC）的存活时间，但RANKL通路与Fas介导的凋亡的关系尚不清楚。在这里，我们发现，骨髓来源的DC（BMDCs）从Fas基因缺陷株MRL/lpr小鼠，可以存活更长的时间比正常的DC。RANKL刺激MRL/lpr小鼠BMDCs后，Bcl-x、Bcl-2的表达及NF-κ B B的核转运均显著上调。相比之下，RANKL刺激可增加正常C57 BL/6和MRL+/+小鼠BMDC的Fas表达，RANKL和抗Fas mAb刺激可增强DC凋亡，这与caspase-3和caspase-9的激活有关。RANKL和抗Fas单克隆抗体可显著降低正常DC中Fas介导的凋亡抑制分子FLIPL的表达。事实上，RANKL刺激的DC的过继转移导致MRL/lpr受体中自身免疫的快速加速。这些结果表明，DC中RANKL和Fas信号之间的串扰可能控制免疫耐受。
Although receptor activator of nuclear factor (NF)-kappa B ligand (RANKL) signaling has been shown to prolong the survival of mature dendritic cells (DCs), the association of RANKL pathway with Fas-mediated apoptosis is obscure. Here, we found that bone marrow-derived DCs (BMDCs) from the Fas-deficient strain MRL/lpr mice, could survive much longer than normal DCs. The expressions of Bcl-x and Bcl-2 and the nuclear transport of NF-kappa B of RANKL-stimulated BMDCs from MRL/lpr mice were significantly upregulated. By contrast, Fas expression of BMDCs from normal C57BL/6 and MRL+/+ mice was increased by RANKL stimulation, and an enhanced DC apoptosis was found when stimulated with both RANKL and anti-Fas mAb, which was associated with activation of caspase-3 and caspase-9. Furthermore, the expression of FLIPL, an inhibitory molecule against Fas-mediated apoptosis, in normal DCs was significantly decreased by RANKL and anti-Fas mAb. Indeed, the adoptive transfer of RANKL-stimulated DCs resulted in rapid acceleration of autoimmunity in MRL/lpr recipients. These findings indicate that the crosstalk between RANKL and Fas signaling in DCs might control immune tolerance.