Inhibition of transmethylation down-regulates CD4 T cell activation and curtails development of autoimmunity in a model system
Inhibition of transmethylation down-regulates CD4 T cell activation and curtails development of autoimmunity in a model system
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DOI：
10.4049/jimmunol.178.8.5366
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发表时间：
2007-04-15
影响因子：
4.4
通讯作者：
Yuan, Chong
中科院分区：
文献类型：
--
作者：
Lawson, Brian R.;Manenkova, Yulia;Yuan, Chong
转甲基化影响几种细胞事件，包括T细胞活化，阻断该途径可减少炎症/自身免疫反应。在这里，我们证明了一种新的可逆的S-腺苷-L-同型半胱氨酸水解酶抑制剂通过减少参与TCR信号传导的几种关键蛋白（包括Akt、Erk 1/2和NF-κ B）的磷酸化而抑制甲基转移，从而导致免疫抑制。值得注意的是，这种作用主要局限于CD 4 T细胞，并与Vav 1（T细胞刺激中必需的鸟嘌呤核苷酸交换因子）的精氨酸甲基化降低相关。用转甲基化抑制剂治疗可以避免，甚至改善CD 4介导的自身免疫性疾病，实验性自身免疫性脑脊髓炎。这些数据表明，转甲基化是CD 4 T细胞活化所必需的，其抑制可能是治疗多发性硬化症和其他CD 4介导的自身免疫性疾病的新方法。
Transmethylation affects several cellular events, including T cell activation, and blockade of this pathway may curtail inflammatory/autoimmune responses. Here, we demonstrate that transmethylation inhibition by a novel reversible S-adenosyl-L-homocysteine hydrolase inhibitor leads to immunosuppression by reducing phosphorylation of several key proteins involved in TCR signaling, including Akt, Erk1/2, and NF-kappa B. Remarkably, this effect was largely restricted to CD4 T cells and correlated with reduced arginine methylation of Vav1, an essential guanine nucleotide exchange factor in T cell stimulation. Treatment with the transmethylation inhibitor averted, and even ameliorated, the CD4-mediated autoimmune disease, experimental autoimmune encephalomyelitis. The data suggest that transmethylation is required for CD4 T cell activation, and its inhibition may be a novel approach in the treatment of multiple sclerosis, and other CD4-mediated autoimmune diseases.