SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production

被引:243
作者
An, Huazhang
Zhao, Wei
Hou, Jin
Zhang, Yan
Xie, Yun
Zheng, Yuejuan
Xu, Hongmei
Qian, Cheng
Zhou, Jun
Yu, Yizhi
Liu, Shuxun
Feng, Gensheng
Cao, Xuetao [1 ]
机构
[1] Second Mil Med Univ, Inst Immunol, Shanghai 200433, Peoples R China
[2] Second Mil Med Univ, Natl Key Lab Med Immunol, Shanghai 200433, Peoples R China
[3] Tsinghua Univ, Sch Med, Inst Immunol, Beijing 100084, Peoples R China
[4] Zhejiang Univ, Inst Immunol, Hangzhou 310031, Peoples R China
[5] Burnham Inst Med Res, La Jolla, CA 92037 USA
基金
中国国家自然科学基金;
关键词
D O I
10.1016/j.immuni.2006.10.014
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The Toll-like receptor 3 (TLR3) and TLR4-signaling pathway that involves the adaptor protein TRIF activates type I interferon (IFN) and proinflammatory cytokine expression. Little is known about how TRIF pathway-dependent gene expression is regulated. SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a widely expressed cytoplasmic tyrosine phosphatase. Here we demonstrate that SHP-2 negatively regulated TLR4- and TLR3-activated IFN-beta production. SHP-2 inhibited TLR3-activated but not TLR2-, TLR7-, and TLR9-activated proinflammatory cytokine IL-6 and TNF-alpha production. SHP-2 inhibited poly(I:C)-induced cytokine production by a phosphatase activity-independent mechanism. C-terminal domain of SHP-2 directly bound TANK binding kinase (TBK1) by interacting with the kinase domain of TBK1. SHP-2 deficiency increased TBK1-activated IFN-beta and TNF-alpha expression. TBK1 knockdown inhibited poly(I:C)-induced IL-6 production in SHP-2-deficient cells. SHP-2 also inhibited poly(I:C)-induced activation of MAP kinase pathways. These results demonstrate that SHP-2 specifically negatively regulate TRIF-mediated gene expression in TLR signaling, partially through inhibiting TBK1-activated signal transduction.
引用
收藏
页码:919 / 928
页数:10
相关论文
共 39 条
[1]   Src homology 2 domain-containing inositol-5-phosphatase 1 (SITP1) negatively regulates TLR4-mediated LPS response primarily through a phosphatase activity- and PI-3K-independent mechanism [J].
An, HZ ;
Xu, HM ;
Zhang, MH ;
Zhou, J ;
Feng, T ;
Qian, C ;
Qi, RZ ;
Cao, XT .
BLOOD, 2005, 105 (12) :4685-4692
[2]   Toll-like receptor signaling pathways [J].
Barton, GM ;
Medzhitov, R .
SCIENCE, 2003, 300 (5625) :1524-1525
[3]   PROTEIN-TYROSINE-PHOSPHATASE SHPTP2 COUPLES PLATELET-DERIVED GROWTH-FACTOR RECEPTOR-BETA TO RAS [J].
BENNETT, AM ;
TANG, TL ;
SUGIMOTO, S ;
WALSH, CT ;
NEEL, BG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (15) :7335-7339
[4]   The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses [J].
Boone, DL ;
Turer, EE ;
Lee, EG ;
Ahmad, RC ;
Wheeler, MT ;
Tsui, C ;
Hurley, P ;
Chien, M ;
Chai, S ;
Hitotsumatsu, O ;
McNally, E ;
Pickart, C ;
Ma, A .
NATURE IMMUNOLOGY, 2004, 5 (10) :1052-1060
[5]   ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance [J].
Brint, EK ;
Xu, DM ;
Liu, HY ;
Dunne, A ;
McKenzie, ANJ ;
O'Neill, LAJ ;
Liew, FY .
NATURE IMMUNOLOGY, 2004, 5 (04) :373-379
[6]   Shp-2 tyrosine phosphatase: Signaling one cell or many [J].
Feng, GS .
EXPERIMENTAL CELL RESEARCH, 1999, 253 (01) :47-54
[7]   IKKε and TBK1 are essential components of the IRF3 signaling pathway [J].
Fitzgerald, KA ;
McWhirter, SM ;
Faia, KL ;
Rowe, DC ;
Latz, E ;
Golenbock, DT ;
Coyle, AJ ;
Liao, SM ;
Maniatis, T .
NATURE IMMUNOLOGY, 2003, 4 (05) :491-496
[8]   The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection [J].
Hemmi, H ;
Takeuchi, O ;
Sato, S ;
Yamamoto, M ;
Kaisho, T ;
Sanjo, H ;
Kawai, T ;
Hoshino, K ;
Takeda, K ;
Akira, S .
JOURNAL OF EXPERIMENTAL MEDICINE, 2004, 199 (12) :1641-1650
[9]   Cutting edge: Repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2 [J].
Hirschfeld, M ;
Ma, Y ;
Weis, JH ;
Vogel, SN ;
Weis, JJ .
JOURNAL OF IMMUNOLOGY, 2000, 165 (02) :618-622
[10]   Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways [J].
Hoebe, K ;
Janssen, EM ;
Kim, SO ;
Alexopoulou, L ;
Flavell, RA ;
Han, JH ;
Beutler, B .
NATURE IMMUNOLOGY, 2003, 4 (12) :1223-1229