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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4685-4692. Prepublished online as a Blood First Edition Paper on February 8, 2005; DOI 10.1182/blood-2005-01-0191. This Article Full Text (PDF) All Versions of this Article: 2005-01-0191v1 105/12/4685    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by An, H. Articles by Cao, X. Search for Related Content PubMed PubMed Citation Articles by An, H. Articles by Cao, X. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 14, 2005 Accepted February 4, 2005 Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1) negatively regulates TLR4-mediated LPS response primarily through phosphatase activity- and PI-3K-independent mechanism Huazhang An, Hongmei Xu, Minghui Zhang, Jun Zhou, Tao Feng, Cheng Qian, Runzi Qi, and Xuetao Cao* Insititute of Immunology, Second Military Medical University, Shanghai, China Insititute of Immunology, Medical School, Tsinghua University, Beijing, China Insititute of Immunology, Zhejiang University, Hangzhou, China Insititute of Immunology, Second Military Medical University, Shanghai, China; Insititute of Immunology, Medical School, Tsinghua University, Beijing, China; Insititute of Immunology, Zhejiang University, Hangzhou, China * Corresponding author; email: caoxt{at}public3.sta.net.cn. Src homology (SH) 2 domain-containing inositol-5-phosphatase 1 (SHIP1) plays important roles in negatively regulating the activation of immune cells primarily via phosphoinositide 3-kinase (PI-3K) pathway by catalyzing PI-3K product PtdIns-3,4,5P3 into PtdIns-3,4P2. However, the role of SHIP1 in TLR4-mediated LPS response remains unclear. Here we demonstrate that SHIP1 negatively regulates LPS-induced inflammatory response via both phosphatase activity-dependent and -independent mechanisms in macrophage. SHIP1 becomes tyrosine phosphorylated and upregulated upon LPS stimulation in RAW264.7 macrophages. SHIP1-specific RNA interfering and SHIP1 overexpression experiments demonstrate SHIP1 inhibits LPS-induced TNF- and IL-6 production by negatively regulating LPS-induced combination between TLR4 and MyD88, activation of Ras, PI-3K, extracellular signal-regulated kinase 1/2 (ERK1/2), p38, c-Jun NH2-terminal kinase (JNK) and degradation of IB-. SHIP1 also significantly inhibits LPS-induced MAPK activation in TLR4-reconstitited COS7 cells. Although SHIP1-mediated inhibition of PI-3K is dependent on its phosphatase activity, phosphatase activity-disrupted mutant SHIP1 remains inhibitory to LPS-induced TNF- production. Neither disrupting phosphatase activity nor using PI-3K pathway inhibitor LY294002 or Wortmannin could significantly block SHIP1-mediated inhibition of LPS-induced ERK1/2, p38 and JNK activation and TNF- production, demonstrating that SHIP1 inhibits LPS-induced activation of MAPKs and cytokine production primarily by phosphatase activity- and PI-3K-independent mechanism. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. M. Sly, M. J. Hamilton, E. Kuroda, V. W. Ho, F. L. Antignano, S. L. Omeis, C. J. van Netten-Thomas, D. Wong, H. K. Brugger, O. Williams, et al. SHIP prevents lipopolysaccharide from triggering an antiviral response in mice Blood, March 26, 2009; 113(13): 2945 - 2954. [Abstract] [Full Text] [PDF] Y. Rui, X. Liu, N. Li, Y. Jiang, G. Chen, X. Cao, and J. Wang PECAM-1 Ligation Negatively Regulates TLR4 Signaling in Macrophages J. Immunol., December 1, 2007; 179(11): 7344 - 7351. [Abstract] [Full Text] [PDF] T. Y. Zhang and R. A. Daynes Macrophages from 11beta-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice Exhibit an Increased Sensitivity to Lipopolysaccharide Stimulation Due to TGF-beta-Mediated Up-Regulation of SHIP1 Expression J. Immunol., November 1, 2007; 179(9): 6325 - 6335. [Abstract] [Full Text] [PDF] Y. Wang, T. Chen, C. Han, D. He, H. Liu, H. An, Z. Cai, and X. Cao Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4 Blood, August 1, 2007; 110(3): 962 - 971. [Abstract] [Full Text] [PDF] C. Qian, H. An, Y. Yu, S. Liu, and X. 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