期刊
JOURNAL OF IMMUNOLOGY
卷 175, 期 7, 页码 4338-4346出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.175.7.4338
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资金
- NCI NIH HHS [CA84488, R01 CA084488, 5P01CA78038, F32CA103393, F32 CA103393, CA100062, R01 CA100062] Funding Source: Medline
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.
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