Correlation between gene polymorphism of macrophage migration inhibitory factor and disease susceptibility: recognition, target and significance

doi:10.3969/j.issn.2095-4344.0299

Abstract

Abstract:

BACKGROUND: Changes in the expression levels of macrophage migration inhibitory factor (MIF) occur in a variety of diseases, and the gene polymorphism of MIF is related to the disease susceptibility and severity. The basic physicochemical properties of MIF, and correlation of MIF gene polymorphism with disease susceptibility are summarized.
OBJECTIVE: To analyze the mechanisms of MIF in various diseases.
METHODS: Databases of PubMed, Sino Med and CNKI were searched by computer for the articles concerning MIF and diseases using the keywords of “MIF, disease, polymorphism” in English and Chinese, respectively. Finally 58 eligible articles were included.
RESULTS AND CONCLUSION: MIF is involved in various diseases such as autoimmune disease, inflammatory disease and cancer. However, MIF plays different roles in various systemic diseases, for example, MIF promotes the secretion of tumor necrosis factor α in adiposities inducing insulin resistance. It also interferes with insulin-mediated NO release from endothelial cells and participates in the development of insulin resistance in endothelial cells. MIF counteracts glucocorticoid effects, restores macrophage factor expression and activates T lymphocytes, which plays an important role in the regulation of inflammatory response. Therefore, to understand the interaction between MIF gene polymorphism and systemic diseases is conducive to the development of basic research on MIF in various systemic diseases. It is of great significance to find MIF as a therapeutic target for various diseases.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Tissue Engineering, Macrophage Migration-Inhibitory Factors, Polymorphism, Single Nucleotide, Immune System Diseases, Neoplasms, Cardiovascular Diseases

CLC Number:

R318

Li Jing1, 2, Peng Yun3, 4, Bao Fu-kai2, 3, 4, 5, 6, Liu Ai-hua3, 4, 5, 6, 7. Correlation between gene polymorphism of macrophage migration inhibitory factor and disease susceptibility: recognition, target and significance[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(28): 4574-4579.

Figures/Tables 1

2.1 MIF概述 2.1.1 MIF基因结构目前已成功克隆出小鼠和人MIF基因，两者基因片段长度均小于1 kb，具有高度同源性[1]。人MIF基因是单拷贝基因，编码基因位于染色体22q11.2，mRNA长度约为0.8 kb，3个外显子被2个短内含子分开，5’端侧翼区存在多个SP-1位点和1个cAMP应答元件(cAMP responsive element，CRE)，而且可在人体多处结构组织中表达。小鼠MIF基因由2个内含子和3个外显子构成，mRNA长度为0.6 kb，其启动子无经典的TATA盒，5’端靠近RNA转录起始位点处存在各种转录因子序列。 2.1.2 MIF来源 MIF的主要是有T细胞产生，小鼠脾细胞和人外周血T淋巴细胞均可检测到MIF mRNA的表达，丝裂原、抗CD3抗体和特异性抗原能促进MIF蛋白的分泌。单核巨噬细胞也是主要分泌MIF的细胞，静息状态下的巨噬细胞可高表达MIF mRNA及MIF前体蛋白，同时发现MIF可以刺激巨噬细胞分泌肿瘤坏死因子α，并协同干扰素γ刺激巨噬细胞产生一氧化氮，从而增强巨噬细胞对感染和组织损伤的反应能力。垂体是MIF蛋白的主要来源，在应激状态下，MIF可随垂体激素促肾上腺皮质激素一起由垂体前叶细胞分泌，并呈时间依赖性增加[1]。 2.2 MIF生物学作用 MIF能够抑制巨噬细胞的迁移，并促进巨噬细胞在炎症局部的聚集、增生、激活、分泌细胞因子，在炎症和内毒素血症中发挥重要作用，其主要生物学作用归纳如下： 2.2.1 抑制糖皮质激素生理效应 MIF具有负反馈调节糖皮质激素的作用，当糖皮质激素水平达免疫抑制效果时，MIF抵抗糖皮质激素效应且恢复巨噬细胞因子表达和使T淋巴细胞活化，在调节炎症反应的调定点和方向中起着重要作用。低浓度的糖皮质激素可以诱导巨噬细胞分泌MIF，并显示为一条钟形的量反应曲线[2]。 2.2.2 抑制p53活性 p53基因是经典肿瘤抑制基因。p53主要从诱导细胞分裂周期停止和凋亡两方面来阻止不适当的细胞增殖。MIF作为p53的负性调节因子，通过抑制p53介导的凋亡或线粒体凋亡等机制，从而促进肿瘤的发展和浸润转移[3-4]。 2.2.3 MIF可调节胰岛素的释放以及糖代谢胰岛β细胞可合成MIF，同胰岛素共同释放进入血液，胰岛β细胞分泌MIF存在自分泌和旁分泌两种产生形式。当人体环境血糖水平过高时，可促进MIF分泌释放，从而促进胰岛素的释放，达到降低血糖的作用。此外，MIF还可促进骨骼肌、心肌对葡萄糖的摄取和利用。在分子层面上，MIF可调节葡萄糖转运体4和磷酸果糖激酶2的浓度；并且MIF还可通过调控肿瘤坏死因子α的表达水平来促进或抑制糖酵解的进程，在应激情况下，该现象更加明显[5-6]。此外，在由于全身炎性反应所引起的血糖改变现象中，MIF与胰岛素受体1和Akt信号通路具有相关性[7]。 2.2.4 炎症免疫调节功能研究发现MIF属于神经内分泌介质，可使宿主对微生物产物产生应答反应，提示MIF是介于内分泌系统和免疫系统之间的因子，具有促炎症免疫功能的能力。在免疫过程中，MIF可促进巨噬细胞在炎症局部浸润、增生及激活并分泌表达一些细胞因子(白细胞介素1β、白细胞介素6、肿瘤坏死因子α及干扰素γ)，同时刺激巨噬细胞使其释放一氧化氮增加和磷脂酶A2的表达增强，从而产生促炎作用[8]。同时MIF能抑制或负调节GC，抑制对免疫和炎性细胞活性及对炎性细胞因子释放，从而起到促炎作用。 2.2.5 酶活性和损伤修复功能 MIF作为羟苯丙酮酸互变异构酶，能催化羟苯丙酮和羟苯丙酮酸的酮基-烯酸互变异构。MIF还可以作为一种蛋白质，巯基氧化还原酶参与氧化还原反应[9]。研究发现在角膜损伤愈合过程中，随着角膜细胞浸润和内皮细胞分化，MIF mRNA表达水平相应升高。有研究发现，在小鼠皮肤损伤愈合过程中，MIF表达水平有升高的趋势，而经抗MIF抗体处理，损伤会推迟愈合[1]。 2.3 MIF启动子多态性与疾病的关系迄今为止，运用高显示液相染色体图谱分析技术已经证明MIF基因在4个位点存在多态性，包括-794区CATT重复序列微卫星多态性位点和3个单核苷酸多态性位点(SNP)：-173区G/C(rs755622)，+254区T/C(rs2096525)及+656区C/G(rs2070766)，其中-794CATT5-8重复序列(rs5844572)和MIF-173G/C单核苷酸多态性(SNP) (rs755622)，已被证实可以影响MIF的基因表达和蛋白水平[10-11]，实际上许多研究已经验证了这两种多态性与各种疾病之间的相关性[12-16]。MIF基因突变引起的功能缺失会扰乱宿主的炎性或固有免疫应答反应机制，从而使宿主出现更严重的炎症和免疫反应。国内外大量研究表明，目前MIF基因多态性主要与炎性疾病、自身免疫性疾病、神经系统疾病和肿瘤的易感性和严重程度相关。研究发现，当人体应激和严重感染时，下丘脑-垂体-肾上腺(HPA)轴激活，血液中ACTH及肾上腺皮质激素水平迅速升高，抑制免疫反应、抵抗应激、保护宿主的作用，血中MIF水平明显升高，且皮质醇和MIF水平在一定范围内成正相关[17]。同时研究显示，MIF在宿主对G-菌毒素(LPS)和G+菌毒素(TSST-1及SPEA)的反应中有重要作用。MIF通过多种信号传导通路，在肿瘤和慢性炎症、自身免疫性疾病、及神经系统疾病等众多疾病中扮演着重要角色，研究MIF基因启动子多态性有利于阐释不同群体对疾病的易感性、严重性及药物抗性等机制(表1)。"

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