Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus.

نویسندگان

  • Gabriela Gorelik
  • Jing Yuan Fang
  • Ailing Wu
  • Amr H Sawalha
  • Bruce Richardson
چکیده

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 PKCdelta or transfection with a dominant negative PKCdelta 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 PKCdelta activation may contribute to the development of idiopathic and hydralazine-induced lupus through effects on T cell DNA methylation.

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عنوان ژورنال:
  • Journal of immunology

دوره 179 8  شماره 

صفحات  -

تاریخ انتشار 2007