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	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
	An, HZ ; Xu, HM ; Zhang, MH ; Zhou, J ; Feng, T ; Qian, C ; Qi, RZ ; Cao, XT
	2010-05-11 ; 2010-05-11
关键词	TOLL-LIKE RECEPTORS FACTOR-KAPPA-B INOSITOL PHOSPHATASE SIGNAL-TRANSDUCTION ENDOTOXIN TOLERANCE GENE-EXPRESSION DENDRITIC CELLS MAST-CELLS SHIP LIPOPOLYSACCHARIDE Hematology
中文摘要	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 (LIPS) 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 LIPS stimulation in RAW264.7 macrophages. SHIP1-specific RNA-interfering and SHIP1 overexpression experiments demonstrate that SHIP1 inhibits LIPS-induced tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) production by negatively regulating the LIPS-induced combination between TLR4 and myeloid differentiation factor 88 (MyD88); activation of Ras (p21(ras) protein), PI-3K, extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase (JNK); and degradation of I kappa B-alpha. 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 LIPS-induced TNF-alpha production. Neither disrupting phosphatase activity nor using the PI-3K pathway inhibitor LY294002 or wortmannin could significantly block SHIP1-mediated inhibition of LIPS-induced ERK1/2, p38, and JNK activation and TNF-alpha production, demonstrating that SHIP1 inhibits LPS-induced activation of MAPKs and cytokine production primarily by a phosphatase activity- and PI-3K-independent mechanism. (c) 2005 by The American Society of Hematology.
语种	英语 ; 英语
出版者	AMER SOC HEMATOLOGY ; WASHINGTON ; 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA
内容类型	期刊论文
源URL	[http://hdl.handle.net/123456789/27564]
专题	清华大学
推荐引用方式 GB/T 7714	An, HZ,Xu, HM,Zhang, MH,et al. 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],2010, 2010.
APA	An, HZ.,Xu, HM.,Zhang, MH.,Zhou, J.,Feng, T.,...&Cao, XT.(2010).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..
MLA	An, HZ,et al."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".(2010).

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