Sphingosine-1-phosphate in allergic responses, asthma and anaphylaxis.
Sphingosine-1-phosphate in allergic responses, asthma and anaphylaxis.
复制标题
DOI：
10.1016/j.pharmthera.2007.05.011
复制
发表时间：
2007-09
影响因子：
13.5
通讯作者：
C. Oskeritzian;S. Milstien;S. Spiegel
中科院分区：
文献类型：
--
作者：
C. Oskeritzian;S. Milstien;S. Spiegel
鞘氨醇-1-磷酸(S1P)是一种生物活性的鞘磷脂代谢物，参与多种细胞过程，不仅作为G蛋白偶联受体的胞外配基，而且作为一种潜在的细胞内信使，具有未知的靶点。肥大细胞是组织寄居的变态反应的关键早期效应者，它可以产生和分泌S1P，该S1P可以与肥大细胞上存在的S1P受体结合，影响其激活和功能。在这篇综述中，我们将首先讨论S1P由两种鞘氨醇激酶(SphK)同工酶产生的现有知识。将讨论SphK的激活机制，重点是开发实验方法来研究它们在肥大细胞中的差异激活和生物学作用。肥大细胞在过敏性疾病、哮喘和过敏反应的病因中的相关性已经得到了很好的证实。在这篇综述中，这一概念将被重新讨论，重点是S1P的产生和分泌在与调节失调的炎症反应相关的症状中的作用。总之，对抗S1P的促炎作用可被视为治疗变态反应性疾病、加重呼吸道炎症和过敏反应的一种治疗策略，并将讨论各种选择，如开发抑制SphKs的药理工具、S1P中和单抗和S1P受体拮抗剂。
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many cellular processes, acting not only as an extracellular ligand to its specific G protein-coupled receptors, but also as a putative intracellular messenger with yet unidentified targets. Mast cells are tissue-dwelling pivotal early effectors of allergic responses, which produce and secrete S1P that can bind to its receptors present on mast cells to influence their activation and functions. In this review, we will first discuss the current knowledge of S1P production by two isozymes of sphingosine kinase (SphK). Mechanisms of SphK activation will be discussed, with an emphasis on experimental approaches developed to study their differential activation and biological roles in the context of mast cells. The relevance of mast cells in the etiology of allergic disorders, asthma and anaphylaxis is well established. In this review, this concept will be revisited, focusing on the contribution of S1P production and secretion to the symptoms associated with dysregulated inflammatory responses. To conclude, counteracting the proinflammatory effects of S1P could be envisioned as a therapeutic strategy to treat allergic disorders, exacerbated airway inflammation, and anaphylactic reactions, and various options will be discussed, such as the development of pharmacological tools to inhibit SphKs, S1P neutralizing monoclonal antibody, and S1P receptor antagonists.