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Tumor-Induced Suppressor of Cytokine Signaling 3 Inhibits Toll-like Receptor 3 Signaling in Dendritic Cells via Binding to Tyrosine Kinase 2

Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, People's Republic of China

Requests for reprints: Rongcun Yang, Department of Immunology, Nankai University School of Medicine, 94 Weijin Road, Tianjin 300071, People's Republic of China. Phone: 86-22-23509007; Fax: 86-22-23502554; E-mail: ryang{at}nankai.edu.cn.

Key Words: SOCS3 • TYK2 • Dendritic cells • IFN

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 IFN. Further, knockdown of SOCS3 transcripts significantly enhanced the responses of RAW264.7 and BMDCs to both polyI:C and IFN. Immunoprecipitation and pull-down studies show that SOCS3 binds to the IFN receptor tyrosine kinase 2 (TYK2). Because polyI:C triggers autocrine IFN signaling, binding of SOCS3 to TYK2 may thereby suppress the activation of BMDCs by polyI:C and IFN. 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 IFN receptor TYK2. [Cancer Res 2008;68(13):5397–404]

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