Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients

Objective. Previous studies have shown that inhibiting T cell DNA methylati on causes a lupus-like disease by modifying gene expression. T cells from p atients with lupus exhibit diminished levels of DNA methyltransferase (MTas e) enzyme activity, hypomethylated DNA, and changes in gene expression simi lar to those exhibited by T cells treated with methylation inhibitors, sugg esting that DNA hypomethylation may contribute to human lupus. Since it is known that DNA MTase levels are regulated by the ras-mitogen-activated prot ein kinase (MAPK) pathway, this study sought to determine whether decreased ras-MAPK signaling could account for the DNA hypomethylation in lupus T ce lls. Methods. DNA MTase messenger RNA (mRNA) from lupus patients and from health y controls was quantitated by Northern analysis, and ras-MAPK signaling was determined by immunoblotting with antibodies to the activated forms of ext racellular receptor-associated kinase (ERK). Results were compared with tho se in T cells in which ras-MAPK signaling was inhibited with a soluble inhi bitor of MAPK ERK 1 (MEK1). Results. T cells from patients with active lupus had diminished DNA MTase m RNA levels and de-creased signaling through the ras-MAPK pathway. Inhibitin g signaling through the ras-MAPK pathway with the MEK1 inhibitor decreased DNA MTase mRNA and enzyme activity to the levels seen in lupus T cells, and resulted in DNA hypomethylation resembling that seen in lupus T cells. Conclusion. These results suggest that a decrease in signaling through the ras-MAPK pathway may be responsible for the decreased MTase activity and DN A hypomethylation in patients with lupus.