Open AccessHydralazine may induce autoimmunity by inhibiting extracellular signal–regulated kinase pathway signaling
Author(s) -
Deng Chun,
Lu Qianjin,
Zhang Zhiyong,
Rao Tharaknath,
Attwood John,
Yung Raymond,
Richardson Bruce
Publication year - 2003
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.10833
Subject(s) - hydralazine , mapk/erk pathway , kinase , signal transduction , mitogen activated protein kinase , p38 mitogen activated protein kinases , protein kinase a , chemistry , cancer research , microbiology and biotechnology , biology , endocrinology , blood pressure
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.