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Roles of G-protein coupled receptors in inflammation and immunity.

G 蛋白偶联受体在炎症和免疫中的作用。

基本信息

批准号：
16390090
负责人：
YOKOMIZO Takehiko
金额：
$ 9.02万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390090/
关键词：
Arachidonic acis leukotriene B4 receptor deficient mice cytokines bronchial asthma delayed-type hyperreactivity pH sensor

项目摘要

Based on the finding that leukotriene B_4 receptor 1 (BLT1) is expressed highly in Th2 lymphocytes, we analyzed the roles of BLT1 using an ovalbumin-induced bronchial asthma model. BLT1-null mice did not develop airway hyperresponsiveness, eosinophilic inflammation and hyperplasia of goblet cells. Attenuated symptoms were accompanied by reduced IgE production, and accumulation of IL-5 and IL-13 in bronchoalveolar lavage fluid, suggesting attenuated Th2-type immune response in BLT1-null mice. Peribronchial lymph node cells of sensitized BLT1-null mice showed much attenuated proliferation and production of Th2 cytokines upon re-stimulation with antigen in vitro. Thus, LTB_4-BLT1 axis is required for the development of Th2-type immune response, and blockade of LTB_4 functions through BLT1 would be novel and useful in the effort to ameliorate bronchial asthma and related Th2-biased immune disorders.Dendritic cells (DCs) are important antigen-presenting cells that control Th1- and Th2-type … More immunological reactions by releasing cytokines and interacting directly with T cells. We found that BLT1 is expressed in human monocyte-derived DCs and mouse bone marrow-derived DCs (BMDCs). Detailed analyses using BMDCs revealed that BLT1-deficient DCs produced less IL-l2 p70 than WT DCs, leading to attenuated IFN-□ production in an allogeneic mixed lymphocyte reaction. Adoptive transfer of BLT1-deficient DCs into naive WT mice induced a weakened. Th1 response and an enhanced Th2 response in vivo compared to WT DCs. BLT1-deficient mice consistently showed much attenuated delayed-type hypersensitivity (DTH), in which Th1-type cellular responses play a key role, and popliteal lymph node cells of BLT1-deficient mice showed reduced production of Th1 cytokines after DTH induction compared to cells from WT mice. Thus, in addition to its role in inflammation, the LTB4-BLT1 axis is important in initiating Th1-type immunological reactions mediated by DCs.We characterized G2A receptor, which was reported as a lysophospholipid receptor, as a proton-sensing GPCR. Less

在此基础上，我们利用卵白蛋白诱导的支气管哮喘模型，分析了白三烯B_4受体1（BLT 1）在Th 2淋巴细胞上的高表达。BLT 1基因敲除小鼠未出现气道高反应性、嗜酸性粒细胞炎症和杯状细胞增生。减轻的症状伴随着IgE产生减少，以及IL-5和IL-13在支气管肺泡灌洗液中的积累，表明BLT 1缺失小鼠中Th 2型免疫应答减弱。致敏的BLT 1-null小鼠的支气管周围淋巴结细胞在体外用抗原再刺激后表现出明显减弱的增殖和Th 2细胞因子的产生。因此，LTB_4-BLT 1轴是Th 2型免疫应答的重要组成部分，通过BLT 1阻断LTB_4轴的功能将有助于改善支气管哮喘及相关的Th 2型免疫紊乱 ...更多信息通过释放细胞因子并直接与T细胞相互作用来进行免疫反应。我们发现BLT 1在人单核细胞来源的DC和小鼠骨髓来源的DC（BMDCs）中表达。使用BMDC的详细分析显示，BLT 1缺陷型DC产生的IL-12 p70比WT DC少，导致同种异体混合淋巴细胞反应中IFN-γ产生减弱。将BLT 1缺陷型DC连续转移到未处理的WT小鼠中诱导了减弱的。Th 1应答和增强的Th 2应答。BLT 1缺陷型小鼠一致表现出明显减弱的迟发型超敏反应（DTH），其中Th 1型细胞反应起着关键作用，与WT小鼠的细胞相比，BLT 1缺陷型小鼠的腘淋巴结细胞在DTH诱导后Th 1细胞因子的产生减少。因此，除了其在炎症中的作用，LTB 4-BLT 1轴是重要的启动Th 1型免疫反应介导的DCs.我们的特点是G2 A受体，这是报告为溶血磷脂受体，作为一个质子敏感的GPCR。少