Lim S P, Leung E, Krissansen G W
Department of Molecular Medicine, School of Medicine and Health Science, University of Auckland, Auckland, New Zealand.
Immunogenetics. 1998 Aug;48(3):184-95. doi: 10.1007/s002510050422.
The beta7 integrins LPAM-1 (alpha4beta7) and M290 (alphaEbeta7) mediate the homing of lymphocytes to gut-associated lymphoid tissue, and the proposed retention of intraepithelial lymphocytes (IEL), respectively. Here we show that the gut mucosal cytokine TGF- beta1 increases the expression of beta7 and alphaE subunit mRNA transcripts and the cell-surface expression of M290 on T cells, and that it decreases the level of alpha4 integrin transcripts. Induced beta7 integrin gene expression was inhibited by the protein tyrosine kinase inhibitor genistein, implicating a role for tyrosine phosphorylation. An analysis of the beta7 integrin gene promoter revealed three DNAse I hypersensitivity sites, two of which mapped to the 5' and 3' ends of a promoter fragment (nucleotides +690 to +63) that directed both the basal and the TGF-beta1-induced expression of a heterologous reporter gene. Deletion analysis identified two TGF-beta1 response regions encompassing nucleotides -509 to -398 (TGFBRR1), and -122 to +32 (TGFBRR2). TGFBRR1 interacted with at least five protein complexes, whose binding could be induced with TGF-beta1 stimulation and could be antagonized by TGFBRR2 which harbored both similar and distinctive cis-elements. TGFBRR2 interacted specifically with at least two major nuclear protein complexes, whose binding was phosphorylation dependent. These data provide new insights into the mechanism by which TGF-beta may switch LPAM-1(+ve) migrating T cells to express M290, facilitating their retention in the gut.
β7整合素LPAM-1（α4β7）和M290（αEβ7）分别介导淋巴细胞归巢至肠道相关淋巴组织以及上皮内淋巴细胞（IEL）的定位。我们在此表明，肠道黏膜细胞因子转化生长因子-β1（TGF-β1）可增加T细胞上β7和αE亚基mRNA转录本的表达以及M290的细胞表面表达，同时降低α4整合素转录本的水平。蛋白酪氨酸激酶抑制剂金雀异黄素可抑制诱导的β7整合素基因表达，提示酪氨酸磷酸化发挥了作用。对β7整合素基因启动子的分析揭示了三个DNA酶I超敏位点，其中两个位于一个启动子片段（核苷酸+690至+63）的5'和3'端，该片段可指导异源报告基因的基础表达以及TGF-β1诱导的表达。缺失分析确定了两个TGF-β1反应区域，分别为核苷酸-509至-398（TGFBRR1）和-122至+32（TGFBRR2）。TGFBRR1与至少五种蛋白质复合物相互作用，其结合可被TGF-β1刺激诱导，并可被含有相似和独特顺式元件的TGFBRR2拮抗。TGFBRR2与至少两种主要的核蛋白复合物特异性相互作用，其结合依赖于磷酸化。这些数据为TGF-β可能将LPAM-1（阳性）迁移T细胞转换为表达M290从而促进其在肠道中定位的机制提供了新的见解。
