Tumor-induced suppressor of cytokine signaling 3 inhibits toll-like receptor 3 signaling in dendritic cells via binding to tyrosine kinase 2.
The suppressor of cytokine signaling (SOCS) family of negative regulatory proteins is up-regulated in response to several cytokines and pathogen-associated molecular patterns (PAMP) and suppresses cellular signaling responses by binding receptor phosphotyrosine residues. Exposure of bone marrow-derived dendritic cells (BMDC) to 1D8 cells, a murine model of ovarian carcinoma, suppresses their ability to express CD40 and stimulate antigen-specific responses in response to PAMPs and, in particular, to polyinosinic acid:poly-CMP (polyI:C) with the up-regulated SOCS3 transcript and protein levels. The ectopic expression of SOCS3 in both the macrophage cell line RAW264.7 and BMDCs decreased signaling in response to both polyI:C and IFNalpha. Further, knockdown of SOCS3 transcripts significantly enhanced the responses of RAW264.7 and BMDCs to both polyI:C and IFNalpha. Immunoprecipitation and pull-down studies show that SOCS3 binds to the IFNalpha receptor tyrosine kinase 2 (TYK2). Because polyI:C triggers autocrine IFNalpha signaling, binding of SOCS3 to TYK2 may thereby suppress the activation of BMDCs by polyI:C and IFNalpha. Thus, elevated levels of SOCS3 in tumor-associated DCs may potentially resist the signals induced by Toll-like receptor 3 ligands and type I IFN to decrease DC activation via binding with IFNalpha receptor TYK2.
Zeng
Bin
B
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, People's Republic of China.
Li
Haijie
H
Liu
Yu
Y
Zhang
Zhuohan
Z
Zhang
Yuan
Y
Yang
Rongcun
R
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016898:Interferon-alpha / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D053634:TYK2 Kinase / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection
D019013:CD40 Antigens; D016898:Interferon-alpha; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse; D011070:Poly I-C