Activation of dendritic cells via inhibition of Jak2/STAT3 signaling.
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-kappaB. This up-regulation was not due to a conventional pathway involving IkappaB 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.
Nefedova
Yulia
Y
Immunology Program, H. Lee Moffitt Cancer Center, and the Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL 33647, USA
Cheng
Pingyan
P
Gilkes
Daniele
D
Blaskovich
Michelle
M
Beg
Amer A
AA
Sebti
Said M
SM
Gabrilovich
Dmitry I
DI
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D053614:Janus Kinase 2; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D000949:Histocompatibility Antigens Class II; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2