Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus.
J Immunol
; 179(8): 5553-63, 2007 Oct 15.
Article
in En
| MEDLINE
| ID: mdl-17911642
ABSTRACT
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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Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes
/
Down-Regulation
/
MAP Kinase Signaling System
/
Extracellular Signal-Regulated MAP Kinases
/
Protein Kinase C-delta
/
Hydralazine
/
Lupus Erythematosus, Systemic
Type of study:
Prognostic_studies
Limits:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
J Immunol
Year:
2007
Document type:
Article
Affiliation country:
United States