Sakai Koichiro, Kitagawa Yoko, Saiki Misuzu, Saiki Shinji, Hirose Genjiro
Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-Machi, Kahoku-Gun, Ishikawa 920-0293,
Mol Immunol. 2003 May;39(14):879-83. doi: 10.1016/s0161-5890(03)00007-5.
The CD154 molecule is important for experimental allergic encephalomyelitis (EAE) which is mediated by autoimmune CD4(+) T-cells. Post-transcriptional instabilization/stabilization of mRNAs, which contain an adenylate uridylate rich element (ARE) in their 3' untranslated region (3'UTR), is regulated in part by binding of ARE-binding proteins to the element. We have investigated the protein which binds to the nonameric ARE in the 3'UTR of CD154 mRNA. A protein which binds to the CD154 ARE was found to exist in a extract prepared from murine autoimmune T-cells activated with myelin basic protein (MBP), and turned out to be mHuR which is a ubiquitous ELAV-like protein. It was found that mHuR was upregulated upon stimulation of the T-cells with a MBP antigen. The CD154 ARE and the ARE in the 3'UTR of tumor necrosis factor-alpha (TNF-alpha) mRNA were competed in binding to mHuR, indicating that both AREs bind to the same site on mHuR. The presence of the CD154 ARE downstream of the luciferase cDNA in a reporter plasmid decreased the translational efficiency, and co-expression of the mHuR slightly increased the translation. These results suggest the possibility that the ELAV-like protein participates in the regulation of the expression of CD154 on the autoimmune T-cells. Modification of the expression of CD154 on autoimmune T-cells by regulating the ELAV-like protein may provide effective therapy for EAE and human multiple sclerosis.
CD154分子对于由自身免疫性CD4(+) T细胞介导的实验性自身免疫性脑脊髓炎（EAE）很重要。3'非翻译区（3'UTR）含有富含腺苷酸尿苷酸元件（ARE）的mRNA的转录后不稳定/稳定化部分受ARE结合蛋白与该元件的结合调控。我们研究了与CD154 mRNA的3'UTR中的九聚体ARE结合的蛋白质。发现一种与CD154 ARE结合的蛋白质存在于用髓鞘碱性蛋白（MBP）激活的小鼠自身免疫性T细胞制备的提取物中，结果证明是mHuR，它是一种普遍存在的ELAV样蛋白。发现用MBP抗原刺激T细胞后mHuR上调。肿瘤坏死因子-α（TNF-α）mRNA的3'UTR中的CD154 ARE和ARE在与mHuR的结合中存在竞争，表明这两个ARE都与mHuR上的同一位点结合。报告质粒中荧光素酶cDNA下游的CD154 ARE的存在降低了翻译效率，而mHuR的共表达略微增加了翻译。这些结果提示ELAV样蛋白可能参与自身免疫性T细胞上CD154表达的调控。通过调节ELAV样蛋白来改变自身免疫性T细胞上CD154的表达可能为EAE和人类多发性硬化症提供有效的治疗方法。
