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Sphingosine 1-phosphate inhibits airway wall remodeling in bronchial asthma

1-磷酸鞘氨醇抑制支气管哮喘气道壁重塑

基本信息

批准号：
15591045
负责人：
ISHIZUKA Tamotsu
金额：
$ 2.24万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591045/
关键词：
Bronchial smooth muscle Airway wall remodeling Sphingosine 1-phosphate Cell migration RANTES Chemokine GTP binding protein Receptor スフィンゴシン1-リン酸リモデリング Rac Gαq 遊走 PDGF TNF Rac1

项目摘要

Sphingosine 1-phosphate(S1P), a bioactive lipid mediator, has been shown to be increased in bronchoalveolar lavage fluid after allergen challenge in asthmatic patients. Here, we examined S1P actions and their intracellular sigallings in cultured human bronchial smooth muscle cells(BSMCs). Expression of mRNAs of three subtypes of S1P receptors, including S1P_1,S1P_2 and S1P_3, were detected in BSMCs, and exposure of the cells to S1P inhibited platelet-derived growth factor(PDGF)-induced migration and tumor necrosis factor-α-induced RANTES production. S1P also inhibited PDGF-induced Rac1 activation, and dominant negative Rac1 inhibited PDGF-induced migration. On the other hand, dominant negative Gα_q attenuated the S1P-induced inhibition of RANTES production. Finally, an S1P_2-selective antagonist JTE-013 suppressed the S1P-induced inhibition of migration response and RANTES production. These results suggest that S1P attenuates cell migration by inhibiting a Rac1-dependent signaling pathway and decreases RANTES production by stimulating a Gα_q-dependent mechanism both possibly through the S1P_2 receptors.

1-磷酸鞘氨醇（S1 P）是一种生物活性脂质介质，在哮喘患者过敏原激发后支气管肺泡灌洗液中增加。在这里，我们研究了S1 P的行动和他们的细胞内信号在培养的人支气管平滑肌细胞（BSMCs）。S1 P可抑制血小板源性生长因子（PDGF）诱导的BSMCs迁移和肿瘤坏死因子-α（TNF-α）诱导的RANTES产生。S1 P还抑制PDGF诱导的Rac 1激活，显性负Rac 1抑制PDGF诱导的迁移。另一方面，显性负性Gα q可减弱S1 P对RANTES产生的抑制作用。S1P_2选择性拮抗剂JTE-013可抑制S1 P对细胞迁移反应和RANTES产生的抑制作用。这些结果表明，S1 P通过抑制Rac 1依赖的信号通路而减弱细胞迁移，通过刺激Gα q依赖的机制而减少RANTES的产生，两者可能均通过S1 P2受体实现。