SOCS3 promotes TLR4 response in macrophages by feedback inhibiting TGF-β1/Smad3 signaling

被引：46
作者：
Liu, Xia [1 ]
Zhang, Yongliang [2 ]
Yu, Yizhi [1 ]
Yang, Xiao [3 ]
Cao, Xuetao [1 ,2 ]
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] Beijing Inst Biotechnol, Beijing 100071, Peoples R China
来源：
MOLECULAR IMMUNOLOGY | 2008年 / 45卷 / 05期
基金：
中国国家自然科学基金;
关键词：
TGF-beta; 1; TLR4; macrophage; SOCS3; cytokine;
D O I：
10.1016/j.molimm.2007.08.018
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Endogenous transforming growth factor-beta1 (TGF-beta 1) plays an important role in the negative regulation of toll-like receptor (TLR) signaling in a feedback manner. Suppressors of cytokine signaling 3 (SOCS3) has been shown to be induced by TGF-beta 1 in osteoclast/macrophage, while the reports on the role of SOCS3 in regulating TLR4 signaling were controversial. The functional relationship between SOCS3 and TGF-beta 1/Smad3 pathway in TLR4 response also remains unclear. In this study, we demonstrate that LPS-induced endogenous TGF-beta 1 contributes to the inducible SOCS3 expression in macrophages. SOCS3 silencing could markedly decrease the LPS-induced production of TNF-alpha and IL-6 in macrophages. Interestingly, less decrease of LPS-induced TNF-alpha, IL-6 by SOCS3 silencing was observed in Smad3 null macrophages. Furthermore, we found SOCS3 could interact with Smad3, and inhibit Smad3 nuclear translocation and transcriptional activity. Therefore, our data demonstrate that SOCS3 is a positive regulator of TLR4 response by feedback inhibiting endogenous TGF-beta 1/Smad3 signaling, thus outlining a new feedback regulatory manner for TLR4 response in macrophages. (c) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码：1405 / 1413
页数：9
相关论文
共 43 条
[1]   c-Ski acts as a transcriptional co-repressor in transforming growth factor-β signaling through interaction with Smads [J].
Akiyoshi, S ;
Inoue, H ;
Hanai, J ;
Kusanagi, K ;
Nemoto, N ;
Miyazono, K ;
Kawabata, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (49) :35269-35277
[2]   SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production [J].
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 .
IMMUNITY, 2006, 25 (06) :919-928
[3]   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
[4]   Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells [J].
Baetz, A ;
Frey, M ;
Heeg, K ;
Dalpke, AH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (52) :54708-54715
[5]   Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation [J].
Berlato, C ;
Cassatella, MA ;
Kinjyo, I ;
Gatto, L ;
Yoshimura, A ;
Bazzoni, F .
JOURNAL OF IMMUNOLOGY, 2002, 168 (12) :6404-6411
[6]   Cross-talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad3 [J].
Blokzijl, A ;
Dahlqvist, C ;
Reissmann, E ;
Falk, A ;
Moliner, A ;
Lendahl, U ;
Ibáñez, CF .
JOURNAL OF CELL BIOLOGY, 2003, 163 (04) :723-728
[7]   Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras [J].
Cacalano, NA ;
Sanden, D ;
Johnston, JA .
NATURE CELL BIOLOGY, 2001, 3 (05) :460-465
[8]   Dendritic cells and CD4+ CD25+ T regulatory cells:: Crosstalk between two professionals in immunity versus tolerance [J].
Chen, WJ .
FRONTIERS IN BIOSCIENCE-LANDMARK, 2006, 11 :1360-1370
[9]   Decorin reverses the repressive effect of autocrine-produced TGF-β on mouse macrophage activation [J].
Comalada, M ;
Cardo, M ;
Xaus, J ;
Valledor, AF ;
Lloberas, J ;
Ventura, F ;
Celada, A .
JOURNAL OF IMMUNOLOGY, 2003, 170 (09) :4450-4456
[10]   Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs [J].
Dalpke, AH ;
Opper, S ;
Zimmermann, S ;
Heeg, K .
JOURNAL OF IMMUNOLOGY, 2001, 166 (12) :7082-7089
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