Key role of ERK pathway signaling in lupus

Abstract

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 δ. Understanding the mechanism causing decreased ERK pathway signaling in lupus may shed light on mechanisms contributing to disease development in genetically predisposed people.

Keywords::

• Lupus T cells
• epigenetics
• DNA methylation
• extracellular signal-regulated kinase pathway signaling
• Protein Kinase δ

Acknowledgements

Declaration of interest: This work was supported by PHS grants AR42525, AG25877 and ES015214, and a Merit grant from the Department of Veterans Affairs. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.