Regulation of anergy-related ubiquitin E3 ligase, GRAIL, in murine models of colitis and patients with Crohn’s disease
Regulation of anergy-related ubiquitin E3 ligase, GRAIL, in murine models of colitis and patients with Crohn’s disease
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DOI：
10.1007/s00535-013-0923-x
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发表时间：
2014-03
影响因子：
6.3
通讯作者：
Akira Mukai;H. Iijima;S. Hiyama;Hironobu Fujii;S. Shinzaki;Takahiro Inoue;Eri Shiraishi;S. Kawai;M. Araki;Y. Hayashi;J. Kondo;T. Mizushima;T. Kanto;S. Egawa;T. Nishida;M. Tsujii;T. Takehara
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作者：
Akira Mukai;H. Iijima;S. Hiyama;Hironobu Fujii;S. Shinzaki;Takahiro Inoue;Eri Shiraishi;S. Kawai;M. Araki;Y. Hayashi;J. Kondo;T. Mizushima;T. Kanto;S. Egawa;T. Nishida;M. Tsujii;T. Takehara
背景：在克罗恩病（CD）的发病机制中，消除耐受性是关键的一步。T细胞能量是耐受的主要机制之一，受淋巴细胞能量相关基因（GRAIL）调控。本研究探讨了GRAIL在CD和小鼠结肠炎模型中的表达及调控。方法研究CD患者、右旋糖酐钠盐（DSS）诱导的结肠炎小鼠和il -10缺乏小鼠外周血和粘膜组织中CD4+T细胞中GRAIL mRNA和蛋白的表达。通过miRNA芯片检测负责GRAIL调控的microrna。将grail过表达的T细胞静脉注射到dss诱导的结肠炎小鼠中。结果GRAIL在CD患者固有层（LP） CD4+T细胞中的表达高于对照组，而在CD患者外周血CD4+T细胞中的表达低于对照组。结肠炎小鼠LP中GRAIL mRNA表达量低于非结肠炎小鼠，而GRAIL蛋白表达量高于非结肠炎小鼠。miRNA微阵列鉴定出miR-290-5p是一种抑制GRAIL蛋白表达的miRNA，在非结肠炎小鼠LP中高表达。grail表达的T细胞表达调节性T细胞标记物，在dss诱导的小鼠结肠炎中表现出抑制作用。结论研究结果表明，在肠黏膜中，GRAIL的表达受特异性miRNA的独特调控，可能与CD的病理生理有关。
BackgroundAbrogating tolerance is a critical step in the pathogenesis of Crohn’s disease (CD). T cell-anergy is one of the main mechanisms of tolerance and is regulated by the gene related to anergy in lymphocytes (GRAIL). This study investigated the expressions and regulation of GRAIL in CD and murine colitis models.MethodsExpressions of GRAIL mRNA and protein in CD4+T cells were investigated in the peripheral blood and mucosal tissues of patients with CD, mice with dextran sodium salt (DSS)-induced colitis, andIl-10-deficient mice. MicroRNAs responsible for the regulation of GRAIL were examined by miRNA microarray. GRAIL-overexpressing T cells were intravenously injected in mice with DSS-induced colitis.ResultsThe GRAIL expression was higher in the lamina propria (LP) CD4+T cells of CD patients than of the control subjects, while it was lower in the peripheral blood CD4+T cells of the CD patients than of the control subjects. The GRAIL mRNA expression was lower, but the GRAIL protein expression was higher in the LP of colitic mice than that of non-colitic mice. The miRNA microarray identified miR-290-5p as an miRNA that inhibits expression of the GRAIL protein and that is highly expressed in the LP of non-colitic mice. GRAIL-expressing T cells expressed regulatory T cell markers and showed suppressive effects in murine DSS-induced colitis.ConclusionsOur results show that expression of GRAIL is uniquely regulated by the specific miRNA in the intestinal mucosa, and suggest that GRAIL may associate with the pathophysiology of CD.