Activation of dendritic cells via inhibition of Jak2/STAT3 signaling

Yulia Nefedova, Pingyan Cheng, Daniele Gilkes, Michelle Blaskovich, Amer A. Beg, Said M. Sebti, Dmitry I. Gabrilovich

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4338-4346
Number of pages9
JournalJournal of Immunology
Volume175
Issue number7
DOIs
StatePublished - Oct 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'Activation of dendritic cells via inhibition of Jak2/STAT3 signaling'. Together they form a unique fingerprint.

Cite this