Hydralazine may induce autoimmunity by inhibiting extracellular signal–regulated kinase pathway signaling

TLDR

Hydralazine‑induced lupus may arise from disrupting ERK pathway signaling, a defect also seen in idiopathic lupus. The study aimed to test whether hydralazine reduces DNA methyltransferase expression and triggers autoimmunity via ERK pathway inhibition. Hydralazine effects were examined in vitro with enzyme inhibition assays and mRNA/activity measurements, and in vivo by treating murine T cells with hydralazine or an ERK inhibitor and assessing anti‑DNA antibody production. Hydralazine failed to inhibit DNMT activity but suppressed ERK signaling, lowering DNMT1/3a expression and activity, and ERK inhibition in T cells induced anti‑dsDNA antibodies, mirroring hydralazine’s lupus‑like effects.

Abstract

Abstract Objective To determine whether hydralazine might decrease DNA methyltransferase (DNMT) expression and induce autoimmunity by inhibiting extracellular signal–regulated kinase (ERK) pathway signaling. Methods The effect of hydralazine on DNMT was tested in vitro using enzyme inhibition studies, and in vivo by measuring messenger RNA (mRNA) levels and enzyme activity. Effects on ERK, c‐Jun N‐terminal kinase, and p38 pathway signaling were tested using immunoblotting. Murine T cells treated with hydralazine or an ERK pathway inhibitor were injected into mice and anti‐DNA antibodies were measured by enzyme‐linked immunosorbent assay. Results In vitro, hydralazine did not inhibit DNMT activity. Instead, hydralazine inhibited ERK pathway signaling, thereby decreasing DNMT1 and DNMT3a mRNA expression and DNMT enzyme activity similar to mitogen‐activated protein kinase kinase (MEK) inhibitors. Inhibiting T cell ERK pathway signaling with an MEK inhibitor was sufficient to induce anti–double‐stranded DNA antibodies in a murine model of drug‐induced lupus, similar to the effect of hydralazine. Conclusion Hydralazine reproduces the lupus ERK pathway signaling abnormality and its effects on DNMT expression, and inhibiting this pathway induces autoimmunity. Hydralazine‐induced lupus could be caused in part by inducing the same ERK pathway signaling defect that occurs in idiopathic lupus.