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

J Immunol. 2007 Oct 15;179(8):5553-63. doi: 10.4049/jimmunol.179.8.5553.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • CD27 Ligand / biosynthesis
  • CD27 Ligand / genetics
  • Cells, Cultured
  • DNA Methylation / drug effects
  • Down-Regulation / immunology*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Hydralazine / pharmacology*
  • Lupus Erythematosus, Systemic / chemically induced*
  • Lupus Erythematosus, Systemic / enzymology
  • Lupus Erythematosus, Systemic / immunology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / immunology*
  • Male
  • Middle Aged
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / drug effects
  • Protein Kinase C-delta / antagonists & inhibitors*
  • Protein Kinase C-delta / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / metabolism


  • CD27 Ligand
  • Protein Kinase Inhibitors
  • Hydralazine
  • Protein Kinase C-delta
  • Extracellular Signal-Regulated MAP Kinases