TY - JOUR
T1 - Activation of dendritic cells via inhibition of Jak2/STAT3 signaling
AU - Nefedova, Yulia
AU - Cheng, Pingyan
AU - Gilkes, Daniele
AU - Blaskovich, Michelle
AU - Beg, Amer A.
AU - Sebti, Said M.
AU - Gabrilovich, Dmitry I.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2005/10/1
Y1 - 2005/10/1
N2 - 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 JS1-124 overcomes the differentiation block induced by TDF and promotes the differentiation of mature DCs and macrophages. Surprisingly, inhibition of Jak2/STAT3 signalling 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-speciflc T cells. Inhibition of Jak2/STATS signaling resulted in activation of the transcription factor NF-κB. This up-regulation was not due to a conventional pathway involving IκBα, but was probably due to a block of the dominant negative effect of STAT3. The 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.
AB - 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 JS1-124 overcomes the differentiation block induced by TDF and promotes the differentiation of mature DCs and macrophages. Surprisingly, inhibition of Jak2/STAT3 signalling 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-speciflc T cells. Inhibition of Jak2/STATS signaling resulted in activation of the transcription factor NF-κB. This up-regulation was not due to a conventional pathway involving IκBα, but was probably due to a block of the dominant negative effect of STAT3. The 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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U2 - 10.4049/jimmunol.175.7.4338
DO - 10.4049/jimmunol.175.7.4338
M3 - Article
C2 - 16177074
AN - SCOPUS:25444444988
SN - 0022-1767
VL - 175
SP - 4338
EP - 4346
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -