Patel D, Gorelik G, Richardson B
Eli Lilly and Company, San Diego, CA, USA; Rheumatology Division, Department of Medicine, University of Michigan, Ann Arbor MI, USA.
Rheumatology Division, Department of Medicine, University of Michigan, Ann Arbor MI, USA.
Lupus (Los Angel). 2016 Dec;1(3). Epub 2016 Dec 30.
Lupus develops when genetically predisposed people encounter certain drugs or environmental agents causing oxidative stress such as infections and sun exposure, and then typically follows a chronic relapsing course with flares triggered by the exogenous stressors. Current evidence indicates that these environmental agents can trigger lupus flares by inhibiting the replication of DNA methylation patterns during mitosis in CD4 T cells, altering the expression of genes suppressed by this mechanism that convert normal "helper" cells into auto reactive cells which promote lupus flares. How environmental stressors inhibit T cell DNA methylation though is incompletely understood. Protein phosphatase 5 (PP5) is a stress induced inhibitor of T cell ERK and JNK signaling in "senescent" CD4CD28 T cells, also characterized by DNA demethylation and altered expression of genes that promote atherosclerosis. We tested if PP5 is increased in CD4CD28 T cells by oxidative stress, if PP5 transfection causes overexpression of methylation sensitive genes in T cells, and if PP5 is overexpressed in lupus T cells.
PP5 was found to be overexpressed in CD4CD28 T cells treated with HO and ONOO- and in T cells from lupus patients.
The results indicate that PP5 increases expression of methylation sensitive T cell genes, and may contribute to the aberrant gene expression in CD4CD28 T cells that characterize lupus flares as well as the aberrant gene expression in CD4CD28 T cells that promote atherosclerosis.
当具有遗传易感性的人接触某些导致氧化应激的药物或环境因素（如感染和日晒）时，就会引发狼疮，随后通常会经历慢性复发过程，外部应激源会引发病情发作。目前的证据表明，这些环境因素可通过抑制CD4 T细胞有丝分裂期间DNA甲基化模式的复制来引发狼疮发作，改变受此机制抑制的基因的表达，从而将正常的“辅助”细胞转化为自身反应性细胞，进而促进狼疮发作。然而，环境应激源如何抑制T细胞DNA甲基化尚不完全清楚。蛋白磷酸酶5（PP5）是“衰老”的CD4CD28 T细胞中应激诱导的T细胞ERK和JNK信号传导抑制剂，其特征还包括DNA去甲基化以及促进动脉粥样硬化的基因表达改变。我们测试了氧化应激是否会使CD4CD28 T细胞中的PP5增加，PP5转染是否会导致T细胞中甲基化敏感基因的过表达，以及狼疮T细胞中PP5是否过表达。
发现在用HO和ONOO-处理的CD4CD28 T细胞以及狼疮患者的T细胞中PP5过表达。
结果表明，PP5会增加甲基化敏感的T细胞基因的表达，可能导致CD4CD28 T细胞中异常基因表达，这种异常基因表达是狼疮发作的特征，同时也会导致促进动脉粥样硬化的CD4CD28 T细胞中出现异常基因表达。
