Lymphocytic cholinergic system and its roles in regulation of immune function

淋巴细胞胆碱能系统及其在免疫功能调节中的作用

基本信息

批准号：
14370037
负责人：
KAWASHIMA Koichiro
金额：
$ 7.49万
依托单位：
Kyoritsu University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Acetylcholine(ACh) is well known as a neurotransmitter in the central and peripheral nervous systems in mammalian species. Both muscarinic and nicotinic ACh receptors(mAChRs and nAChRs, respectively) have been identified in lymphocytes, and their stimulation by mAChR and nAChR agonists elicits a variety of functional and biochemical effects. On the basis of these findings, it has been postulated that the parasympathetic nervous system may play a role in immune-neurohumoral crosstalk. However, we discovered that lymphocytes express most components of the cholinergic system, such as various subtypes of mAChRs and nAChRs, ACh, choline acetyltransferase(ChAT), high affinity choline transporter and acetylcholinesterase. Furthermore, we have observed that ACh and mAChR agonists elicit intracellular Ca^<2+> signaling, up-regulation of c-fos expression and nitric oxide synthesis within T and B cells, probably via M_3 and M_5 mAChRs. Stimulation of nAChRs with ACh or nicotine caused rapid and transient Ca^<2+> signaling in T and B cells, probably via α7 nAChR subunit-mediated pathways. Phytohemagglutinin- or antigen-induced T cell activation via cell surface molecules(e.g., T cell receptor/CD3 complexes) enhances lymphocytic cholinergic transmission by up-regulating ChAT and M_5 mAChR expression, suggesting that a local lymphocytic cholinergic system is involved in regulating immune function. This idea is supported by the findings that lymphocytic cholinergic activity is altered in animal models exhibiting immunological abnormalities. In addition, it appears likely that during interactions mediated by cell surface molecules T cells communicate via ACh with thymic epithelial cells and vascular endothelial cells, which also express ChAT and nAChRs or mAChRs. Collectively, the data we obtained provide a compelling picture in which lymphocytes constitute a cholinergic system that is independent of cholinergic nerves, and which is involved in the regulation of immune function.

乙酰胆碱（ACH）在哺乳动物物种的中央和周围神经系统中被称为神经递质。在淋巴细胞中已经鉴定出毒蕈碱和烟碱ACH受体（分别为MACHR和NACHR），MACHR和NACHR激动剂的刺激引起了各种功能和生化作用。根据这些发现，已经假定副交感神经系统可能在免疫 - 神经瘤串扰中发挥作用。但是，我们发现淋巴细胞表达胆碱能系统的大多数成分，例如MACHR和NACHR的各种亚型，ACH，胆碱乙酰基转移酶（CHAT），高亲和力胆碱转运蛋白和乙酰胆碱酯酶。此外，我们已经观察到ACH和MACHR激动剂会引起细胞内Ca^<2+>信号传导，C-FOS表达的上调和T和B细胞内的一氧化氮合成，可能是通过M_3和M_5 MACHR。用ACH或尼古丁刺激NACHR在T和B细胞中引起快速和瞬态的Ca^<2+>信号传导，这可能是通过α7NACHR亚基介导的途径。通过细胞表面分子（例如，T细胞受体/CD3复合物）通过上调聊天和M_5 MACHR表达来增强淋巴细胞胆碱能的传播，通过上调聊天和M_5 MACHR表达增强淋巴细胞胆碱能的传播，这表明局部淋巴细胞胆碱能系统涉及监管Immunorore功能，从而增强了淋巴细胞胆碱能的传播。在表现出免疫学异常的动物模型中，淋巴细胞胆碱能活性改变的发现支持了这一想法。此外，在细胞表面分子介导的相互作用中，T细胞通过胸腺上皮细胞和血管内皮细胞通过ACH进行通信，这些细胞也表达聊天和NACHRS或MACHR。总的来说，我们获得的数据提供了令人信服的图片，其中淋巴细胞构成了独立于胆碱能神经的胆碱能系统，并且参与了免疫功能的调节。