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

被引:119
作者
An, HZ
Xu, HM
Zhang, MH
Zhou, J
Feng, T
Qian, C
Qi, RZ
Cao, XT
机构
[1] Mil Med Univ 2, Inst Immunol, Shanghai 200433, Peoples R China
[2] Tsing Hua Univ, Sch Med, Inst Immunol, Beijing 100084, Peoples R China
[3] Zhejiang Univ, Inst Immunol, Hangzhou 310027, Peoples R China
关键词
D O I
10.1182/blood-2005-01-0191
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
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.
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页码:4685 / 4692
页数:8
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