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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 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 Citation Map 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. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1) negatively regulates TLR4-mediated LPS response primarily through a phosphatase activity- and PI-3K-independent mechanism Huazhang An, Hongmei Xu, Minghui Zhang, Jun Zhou, Tao Feng, Cheng Qian, Runzi Qi, and Xuetao Cao From the Institute of Immunology, Second Military Medical University, Shanghai, People's Republic of China; Institute of Immunology, Medical School, Tsinghua University, Beijing, People's Republic of China; and Institute of Immunology, Zhejiang University, Hangzhou, People's Republic of China. Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) plays important roles in negatively regulating the activation of immune cells primarily via the phosphoinositide 3-kinase (PI-3K) pathway by catalyzing the PI-3K product PtdIns-3,4,5P3 (phosphatidylinositol-3,4,5-triphosphate) into PtdIns-3,4P2. However, the role of SHIP1 in Toll-like receptor 4 (TLR4)-mediated lipopolysaccharide (LPS) response remains unclear. Here we demonstrate that SHIP1 negatively regulates LPS-induced inflammatory response via both phosphatase activity-dependent and -independent mechanisms in macrophages. SHIP1 becomes tyrosine phosphorylated and up-regulated upon LPS stimulation in RAW264.7 macrophages. SHIP1-specific RNA-interfering and SHIP1 overexpression experiments demonstrate that SHIP1 inhibits LPS-induced tumor necrosis factor (TNF-) and interleukin 6 (IL-6) production by negatively regulating the LPS-induced combination between TLR4 and myeloid differentiation factor 88 (MyD88); activation of Ras (p21ras protein), PI-3K, extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase (JNK); and degradation of IB-. SHIP1 also significantly inhibits LPS-induced mitogen-activated protein kinase (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 the 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 a phosphatase activity- and PI-3K-independent mechanism. (Blood. 2005;105:4685-4692) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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. 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