Sphingosine kinase signalling in immune cells: Potential as novel therapeutic targets
Sphingosine kinase signalling in immune cells: Potential as novel therapeutic targets
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DOI：
10.1016/j.bbapap.2007.07.013
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Melendez, Ahrio J.
中科院分区：
文献类型：
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作者：
Melendez, Ahrio J.
在过去的几年中，人们已经清楚鞘脂是重要信号分子的来源。特别是，鞘脂代谢物神经酰胺和 S1P 已成为一类新的有效生物活性分子，参与细胞分化、凋亡和增殖等多种细胞过程。鞘磷脂 (SM) 是主要的膜鞘脂，也是生物活性产品的前体。神经酰胺是通过鞘磷脂酶 (SMase) 的作用从 SM 形成的，然而，神经酰胺可以被神经酰胺酶非常快速地水解，产生鞘氨醇，并且鞘氨醇可以被鞘氨醇激酶 (SphK) 磷酸化，产生 S1P。在免疫细胞中，鞘脂代谢与免疫细胞发育、分化、激活和增殖的主要阶段密切相关，并转化为生存、钙动员、细胞骨架重组和趋化性等生理反应。多种生物效应物已被证明可以促进 S1P 的合成，包括生长因子、细胞因子以及抗原和 G 蛋白偶联受体激动剂。最近对 S1P 的兴趣集中在这种脂质的两种不同的细胞作用上，即它作为细胞内第二信使的功能，能够触发内部储存的钙释放，以及作为激活特定 G 蛋白偶联受体的细胞外配体。抑制 SphK 刺激可强烈减少甚至阻止由几种促炎激动剂触发的细胞事件，例如受体刺激的 DNA 合成、Ca2+ 动员、脱颗粒、趋化性和细胞因子产生。另一个非常重要的观察结果是 S1P 在趋化性和细胞凋亡逃逸中发挥的直接作用。作为一种细胞外介质，多项研究现已表明，S1P 与许多由内皮分化基因 (EDG) 编码的 G 蛋白偶联受体 (GPCR) 结合，统称为 S1P 受体。 S1P 与这些受体的结合引发广泛的细胞反应，包括增殖、增强细胞外基质组装、刺激粘附连接、形成肌动蛋白应激纤维以及抑制由神经酰胺或生长因子撤回诱导的细胞凋亡。此外，阻断 SIPI 受体可抑制淋巴细胞从淋巴器官流出。本综述总结了将 SphK 信号通路与免疫细胞激活联系起来的证据，并基于这些数据讨论了靶向 SphK 抑制炎症和其他病理状况的潜力。 (C) 2007 Elsevier B.V. 保留所有权利。
During the last few years, it has become clear that sphingolipids are sources of important signalling molecules. Particularly, the sphingolipid metabolites, ceramide and S1P, have emerged as a new class of potent bioactive molecules, implicated in a variety of cellular processes such as cell differentiation, apoptosis, and proliferation. Sphingomyelin (SM) is the major membrane sphingolipid and is the precursor for the bioactive products. Ceramide is formed from SM by the action of sphingomyelinases (SMase), however, ceramide can be very rapidly hydrolysed, by ceramidases to yield sphingosine, and sphingosine can be phosphorylated by sphingosine kinase (SphK) to yield S1P. In immune cells, the sphingolipid metabolism is tightly related to the main stages of immune cell development, differentiation, activation, and proliferation, transduced into physiological responses such as survival, calcium mobilization, cytoskeletal reorganization and chemotaxis. Several biological effectors have been shown to promote the synthesis of S1P, including growth factors, cytokines, and antigen and G-protein-coupled receptor agonists. Interest in S1P focused recently on two distinct cellular actions of this lipid, namely its function as an intracellular second messenger, capable of triggering calcium release from internal stores, and as an extracellular ligand activating specific G protein-coupled receptors. Inhibition of SphK stimulation strongly reduced or even prevented cellular events triggered by several proinflammatory agonists, such as receptor-stimulated DNA synthesis, Ca2+ mobilization, degranulation, chemotaxis and cytokine production. Another very important observation is the direct role played by S1P in chemotaxis, and cellular escape from apoptosis. As an extracellular mediator, several studies have now shown that S1P binds a number of G-protein-coupled receptors (GPCR) encoded by endothelial differentiation genes (EDG), collectively known as the S1P-receptors. Binding of S1P to these receptors trigger an wide range of cellular responses including proliferation, enhanced extracellular matrix assembly, stimulation of adherent junctions, formation of actin stress fibres, and inhibition of apoptosis induced by either ceramide or growth factor withdrawal. Moreover, blocking SIPI-receptor inhibits lymphocyte egress from lymphatic organs. This review summarises the evidence linking SphK signalling pathway to immune-cell activation and based on these data discuss the potential for targeting SphKs to suppress inflammation and other pathological conditions. (C) 2007 Elsevier B.V. All rights reserved.