骨形态发生蛋白2信号对肿瘤组织中调节性T细胞分化和浸润的作用  

Effects of Signaling Activation of Bone Morphogenetic Protein 2 on the Differentiation and Infiltration of Regulatory T Lymphocytes in Tumors

作　　者：黄菲[1] 王海[2] 陈尧清 吴贵[2] HUANG Fei;WANG Hai;CHEN Yaoqing;WU Gui(Central Lab,the First Affiliated Hospital of Fujian Medical University,Fuzhou 350005,China;Department of Orthopedics,the First Affiliated Hospital of Fujian Medical University,Fuzhou 350005,China)

机构地区：[1]福建医科大学附属第一医院中心实验室,福建福州350005 [2]福建医科大学附属第一医院骨科,福建福州350005

出　　处：《中国医学科学院学报》2021年第6期897-904,共8页Acta Academiae Medicinae Sinicae

基　　金：福建省科技创新联合资金(2018Y9086)。

摘　　要：目的明确骨形态发生蛋白2(BMP2)信号是否通过增强髓样抑制性细胞(MDSC)分泌转化生长因子β(TGF-β)诱导肿瘤组织调节性T淋巴细胞(Treg)的分化和浸润。方法通过实时荧光定量PCR检测BMP2信号诱导MDSC的TGF-βmRNA表达水平,应用酶联免疫吸附实验检测BMP2信号诱导MDSC分泌的TGF-β蛋白水平。应用流式细胞术检测BMP2信号诱导MDSC分泌的TGF-β对Treg分化的影响。将人源重组骨形态发生蛋白2(rhBMP2)材料埋植于荷瘤小鼠体内以检测生物体内BMP2通过诱导MDSC分泌TGF-β对Treg细胞活化的作用,应用酶联免疫吸附实验检测外周血和肿瘤组织中的TGF-β蛋白水平,应用免疫荧光检测Treg细胞在肿瘤组织中的浸润情况。结果BMP2在体外可以促进MDSC TGF-βmRNA和蛋白水平表达升高,BMP2信号诱导MDSC分泌的TGF-β可于体外诱导Treg细胞分化。rhBMP2的局部埋植可以促进小鼠外周血和肿瘤组织TGF-β蛋白水平的升高,且可促进Treg细胞浸润肿瘤组织。结论BMP2信号通过促进MDSC分泌TGF-β诱导Treg的分化,并诱导肿瘤组织Treg细胞的浸润。Objective To determine whether the signaling activation of bone morphogenetic protein 2(BMP2)can induce myeloid-derived suppressor cells(MDSC)to secret transforming growth factorβ(TGF-β),further enhancing the differentiation and infiltration of regulatory T lymphocytes(Treg)into tumor tissue.Methods The BMP2-induced mRNA and protein expression of TGF-βin MDSC was detected by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay(ELISA),respectively.The effect of BMP2-induced TGF-βsecretion by MDSC on Treg differentiation was then determined by flow cytometry.Finally,we implanted the recombined human bone morphogenetic protein 2(rhBMP2)collagen gels into tumor-burdened mice to examine the role of BMP2 in Treg differentiation via MDSC-secreted TGF-βin vivo.The protein levels of TGF-βin peripheral blood and tumor tissue were detected by ELISA,and the infiltration of Treg cells in tumor tissue was detected by immunofluorescence assay.Results BMP2 up-regulated the mRNA and protein levels of TGF-βin MDSC in vitro.TGF-βsecreted by the MDSC exposed to BMP2 treatment could induce the differentiation of Treg cells in vitro.Local implantation of rhBMP2 could increase the level of TGF-βprotein in peripheral blood and tumor tissue of mice,further enhancing the infiltration of Treg cells into tumors.Conclusion BMP2 signaling activation can induce the differentiation of Treg cells by promoting the secretion of TGF-βin MDSC,and subsequently promote the infiltration of Treg cells into tumors.

关 键 词：骨形态发生蛋白2 髓样抑制性细胞 调节性T淋巴细胞 肿瘤 

分 类 号：R392.12[医药卫生—免疫学]