Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus.
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.
Gorelik
Gabriela
G
Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Fang
Jing Yuan
JY
Wu
Ailing
A
Sawalha
Amr H
AH
Richardson
Bruce
B
D000328:Adult; D000368:Aged; D053282:CD27 Ligand / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D015536:Down-Regulation / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000201:enzymology / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism
D053282:CD27 Ligand; D047428:Protein Kinase Inhibitors; D006830:Hydralazine; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases