Key role of ERK pathway signaling in lupus.
Systemic lupus erythematosus is a poorly understood autoimmune disease, characterized by autoantibodies to nuclear antigens and immune complex deposition in organs like the kidney. Current evidence indicates that a pathologic CD4+T cell subset, characterized by impaired extracellular signal-regulated kinase (ERK) pathway signaling, DNA hypomethylation, and consequent aberrant gene expression contributes to disease pathogenesis. Hydralazine is a lupus-inducing drug that also decreases T cell DNA methylation by inhibiting the ERK signaling pathway, replicating the defect found in lupus T cells. These observations suggest that defective ERK pathway signaling alters gene expression in T cells by inhibiting DNA methylation, contributing to lupus pathogenesis. The signaling defect in hydralazine-treated and lupus T cells has now been mapped to protein kinase C delta. Understanding the mechanism causing decreased ERK pathway signaling in lupus may shed light on mechanisms contributing to disease development in genetically predisposed people.
Gorelik
Gabriela
G
Department of Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA. ggorelik@umich.edu
Richardson
Bruce
B
D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D019175:DNA Methylation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D020935:MAP Kinase Signaling System; D051745:Protein Kinase C-delta / Q000276:immunology / Q000378:metabolism
D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases