Activation of dendritic cells via inhibition of Jak2/STAT3 signaling
Activation of dendritic cells via inhibition of Jak2/STAT3 signaling
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DOI：
10.4049/jimmunol.175.7.4338
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发表时间：
2005-10-01
影响因子：
4.4
通讯作者：
Gabrilovich, DI
中科院分区：
文献类型：
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作者：
Nefedova, Y;Cheng, PY;Gabrilovich, DI
通过Jak2/STAT3信号传导对正常树突状细胞（DC）分化至关重要。此外，我们之前已经证明，由肿瘤衍生因子（TDF）诱导的Jak2/STAT3通路的过度激活可能是导致癌症DC分化异常的原因。在这项研究中，我们使用一种新的Jak2/STAT3选择性抑制剂JSI-124，研究了Jak2/STAT3对dc和dc的作用机制。肿瘤DC分化的药理调控可能性。我们的实验表明，JSI-124克服了TDF诱导的分化阻滞，促进了成熟dc和巨噬细胞的分化。令人惊讶的是，Jak2/STAT3信号的抑制导致在TDF存在和对照培养基中产生的未成熟dc的显著激活。这种激活表现为MHC II类共刺激分子的上调，以及刺激同种异体或ag特异性T细胞的能力的急剧增加。Jak2/ STAT3信号的抑制导致转录因子NF-kappa B的激活，这种上调不是由于涉及I kappa B α的常规途径，而可能是由于STAT3的主要负作用被阻断。这表明Jak2/STAT3在DC激活的负调控中发挥重要作用，通过药理抑制Jak2/STAT3通路可以增强DC功能。
Signaling via Jak2/STAT3 is critically important for normal dendritic cell (DC) differentiation. In addition, we have previously demonstrated that hyperactivation of the Jak2/STAT3 pathway induced by tumor-derived factors (TDF) may be responsible for abnormal DC differentiation in cancer. In this study, using a novel selective inhibitor of Jak2/STAT3, JSI-124, we investigated the mechanism of the Jak2/STAT3 effect on DCs and the. possibility of pharmacological regulation of DC differentiation in cancer. Our experiments have demonstrated that JSI-124 overcomes the differentiation block induced by TDF and promotes the differentiation of mature DCs and macrophages. Surprisingly, inhibition of Jak2/STAT3 signaling resulted in dramatic activation of immature DCs generated in the presence of TDF as well as in control medium. This activation manifested in up-regulation of MHC class II, costimulatory molecules, and a dramatic increase in the ability to stimulate allogeneic or Ag-specific T cells. Inhibition of Jak2/ STAT3 signaling resulted in activation of the transcription factor NF-kappa B This up-regulation was not due to a conventional pathway involving I kappa B alpha, but was probably due to a block of the dominant negative effect of STAT3. This indicates that Jak2/ STAT3 play an important role in negative regulation of DC activation, and pharmacological inhibition of the Jak2/STAT3 pathway can be used to enhance DC function.