Impaired T cell protein kinase Cδ activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus
Impaired T cell protein kinase Cδ activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus
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DOI：
10.4049/jimmunol.179.8.5553
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Richardson, Bruce
中科院分区：
文献类型：
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作者：
Gorelik, Gabriela;Fang, Jing Yuan;Richardson, Bruce
狼疮患者的T细胞或用狼疮诱导药物肼治疗的T细胞有ERK磷酸化缺陷。信号转导受损的原因尚不清楚，但有必要阐明，因为在动物模型中，T细胞ERK通路信号的减少通过降低DNA甲基转移酶的表达，导致DNA低甲基化和甲基化敏感基因的过表达，从而导致狼疮样疾病，从而导致自身反应性和自身免疫。因此，我们分析了PMA在狼疮患者CD4(+) T细胞和肼处理细胞中刺激的ERK通路磷酸化级联反应。这些细胞中的缺陷定位于蛋白激酶C (PKC) δ。药理抑制PKC δ或转染显性阴性PKCS突变体导致TNFSF7 （CD70）启动子去甲基化和CD70过表达，类似于狼疮和肼处理的T细胞。这些结果表明，有缺陷的T细胞PKC δ激活可能通过影响T细胞DNA甲基化来促进特发性和肼诱导狼疮的发展。
T cells from patients with lupus or treated with the lupus-inducing drug hydralazine have defective ERK phosphorylation. The reason for the impaired signal transduction is unknown but important to elucidate, because decreased T cell ERK pathway signaling causes a lupus-like disease in animal models by decreasing DNA methyltransferase expression, leading to DNA hypomethylation and overexpression of methylation-sensitive genes with subsequent autoreactivity and autoimmunity. We therefore analyzed the PMA stimulated ERK pathway phosphorylation cascade in CD4(+) T cells from patients with lupus and in hydralazine-treated cells. The defect in these cells localized to protein kinase C (PKC)delta. Pharmacologic inhibition of PKC delta or transfection with a dominant negative PKCS mutant caused demethylation of the TNFSF7 (CD70) promoter and CD70 overexpression similar to lupus and hydralazine-treated T cells. These results suggest that defective T cell PKC delta activation may contribute to the development of idiopathic and hydralazine-induced lupus through effects on T cell DNA methylation.