蛋氨酸脑啡肽通过阿片受体调节CD8+T细胞活性机理的研究

Mechanism of regulation on immune cells mediated by methionine enkephalin via binding opioid receptor. MENK,a pentapeptide,composed of Tye-Ala-Ala-Phe-Met, is derived from pre-enkephalin and circulates in blood at low concentration. The data from both previous studies and published results of our laboratory indicate that MENK at physiological concentration exerts positive immunoregulation on various types of immune cells, such as: augmenting the interactions between dendritic cells(DCs) and CD4+T helper 1 cells, inducing phenotypic and functional differentiation of DCs with increased antigen presentation, inducing polarization of macrophages to the M1phenotyp and eliciting CD8+T cell cytotoxicity. In addition, there have been numerous studies indicating that MENK treatment of syngeneic and xenogeneic tumors can induce inhibition of tumor growth. Also we find that MENK could inhibit regulatory T cell(Treg). Other data show that MENK can play role of immunoregulation, as evidenced by enhancing T cell and NK cell proliferation, even directly inhibiting tumor growth through binding to receptor on tumor cell. However, little attention has been given to the molecular mechanisms that are involved. Especially which type of opioid receptor is responsible for trggering this regulation and what is signal linker between opioid receptors and immune molecules inside cells. . These mechanisms arouse our interesting to dig in depth. These are key issues to be solved. So we write this proposal to do a systemic approach to elucidate related mechanism of detailed regulation on immune cells by MENK, so as to provide theoretic evidence to support clinical application of MENK as a drug of anticancer or immunoregulation in the future.Also we believe this meaningful approach is helpful to the better understanding of connection between endocrine system and immune system.

蛋氨酸脑啡肽(Methionine Enkephalin,MENK)是体内自然生成，同时调节神经内分泌和免疫系统的重要物质，现已人工合成。近年来研究发现人体内免疫系统细胞表面也存在阿片受体。研究证明MENK通过免疫细胞上的阿片受体激活免疫细胞，发挥持久免疫调节和抗肿瘤作用，临床具有广阔前景。我的实验室发表大量文章也证明了这一点。阿片受体有δ，μ 和κ三种，究竟MENK通过哪一种受体，如何通过阿片受体胞内信号与免疫信号连接调节免疫细胞活性和发挥抗肿瘤作用，是本研究要解决的科学问题。本研究将全面阐明MENK如何通过免疫细胞上哪一种阿片受体发挥抗免疫调节作用，帮助全面理解内分泌系统和免疫系统之间关系，也为临床用MENK进行免疫治疗提供理论依据，因而具有重要理论和实际意义。

蛋氨酸脑啡肽（Methionine enkephalin，MENK）是由肾上腺产生的前脑啡肽衍生出来的五肽，它不仅可调节神经内分泌活性，也可与多种细胞表面阿片受体结合产生不同的免疫效应。本项目在体外实验主要研究MENK通过调控阿片受体亚基对CD8+T细胞功能的影响；体内实验主要研究MENK对C57BL/6荷瘤小鼠脾中CD8+T细胞转录组的影响，以及对lncRNA及mRNA的差异基因表达的影响，找出MENK调控CD8+T细胞的信号通路。研究表明：1）MENK通过上调μ和δ阿片受体调控CD8+T细胞的增殖和功能表型，这种调控作用可以在μ或δ单独或同时被阻断时消失；2）MENK对S180肉瘤具有显著的抗肿瘤效果，可提高荷瘤鼠脾和淋巴结中CD8+T细胞的比例；3）MENK治疗能够显著影响荷瘤鼠脾中CD8+T细胞转录组中mRNA及lncRNA的表达，可能通过阿片受体介导的Ras pathway参与调控CD8+T细胞的生物学作用。本研究为应用MENK进行免疫调节以及抗肿瘤治疗，深入了解MENK对免疫细胞的调控机制提供了实验依据，具有十分重要的理论价值和指导意义。