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

作     者：An H Xu H Zhang M Zhou J Feng T Qian C Qi R Cao X 

作者机构：Institute of Immunology Second Military Medical Universlty Shanghai 200433 China 

出 版 物：《第二军医大学学报》 (Academic Journal of Second Military Medical University)

年 卷 期：2006年第27卷第1期

页      面：45-45页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 

主　　题：同源关系 肌醇-5-磷酸酶1 酶活性 生物学 

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 Ptdlns-3,4,5P3 (phosphatidylinositol 3,4,5-triphosphate) into Ptdlns-3,4P2. However, the role of SHIP1 in Toll-like receptor 4 (T1.R4)-mediated lipopolysaccharide (LPS) response remains unclear. Here we demonstrate that SHIP1 negatively regulates ***-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. SHIPl- specific RNA-interfering and SHIP1 overexpression experiments demonstrate that SHIP1 inhibits ***-induced tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) production by negatively regulating the LPS-induced combination between T1.R4 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 klnase (JNK) ; and degradation of lkappaB-alpha. SHIP1 also significantly inhibits *** induced mitogen-activated protein kinase (MAPK) activation in TLR4-reconstitited COS7 cells. Although SHIPl-mediated inhibition of PI-3K is dependent on its phosphatase activity, phosphatase activity-disrupted mutant SHIP1 remains inhibitory to LPS-induced TNF-alpha production. Neither disrupting phosphatase activity nor using the PI-3K pathway inhibitor I.Y294002 or wortmannin could significantly block SH1P1-mediated inhibition of LPS-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.