Previous studies have shown that inhibiting T cell DNA methylation causes a lupus‐like disease by modifying gene expression. T cells from patients with lupus exhibit diminished levels of DNA methyltransferase (MTase) enzyme activity, hypomethylated DNA, and changes in gene expression similar to those exhibited by T cells treated with methylation inhibitors, suggesting that DNA hypomethylation may contribute to human lupus. Since it is known that DNA MTase levels are regulated by the ras–mitogen‐activated protein kinase (MAPK) pathway, this study sought to determine whether decreased ras‐MAPK signaling could account for the DNA hypomethylation in lupus T cells.

DNA MTase messenger RNA (mRNA) from lupus patients and from healthy controls was quantitated by Northern analysis, and ras‐MAPK signaling was determined by immunoblotting with antibodies to the activated forms of extracellular receptor–associated kinase (ERK). Results were compared with those in T cells in which ras‐MAPK signaling was inhibited with a soluble inhibitor of MAPK ERK 1 (MEK1).

T cells from patients with active lupus had diminished DNA MTase mRNA levels and decreased signaling through the ras‐MAPK pathway. Inhibiting 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.

These results suggest that a decrease in signaling through the ras‐MAPK pathway may be responsible for the decreased MTase activity and DNA hypomethylation in patients with lupus.