Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs.
Exposing genetically predisposed individuals to certain environmental agents is believed to cause human lupus. How environmental agents interact with the host to cause lupus is poorly understood. Procainamide and hydralazine are drugs that cause lupus in genetically predisposed individuals. Understanding how these environmental agents cause lupus may indicate mechanisms relevant to the idiopathic disease. Abnormal T cell DNA methylation, a repressive epigenetic DNA modification, is implicated in procainamide and hydralazine induced lupus, as well as idiopathic lupus. Procainamide is a competitive DNA methyltransferase (Dnmt) inhibitor, hydralazine inhibits ERK pathway signaling thereby decreasing Dnmt expression, and in lupus T cells decreased ERK pathway signaling causing a similar Dnmt decrease. T cells treated with procainamide, hydralazine, and other Dnmt and ERK pathway inhibitors cause lupus in mice. Whether the same genetic regulatory elements demethylate in T cells treated with Dnmt inhibitors, ERK pathway inhibitors, and in human lupus is unknown. CD70 (TNFSF7) is a B cell costimulatory molecule overexpressed on CD4(+) lupus T cells as well as procainamide and hydralazine treated T cells, and contributes to excessive B cell stimulation in vitro and in lupus. In this report we identify a genetic element that suppresses CD70 expression when methylated, and which demethylates in lupus and in T cells treated with Dnmt and ERK pathway inhibitors including procainamide and hydralazine. The results support a model in which demethylation of specific genetic elements in T cells, caused by decreasing Dnmt expression or inhibiting its function, contributes to drug-induced and idiopathic lupus through altered gene expression.
Lu
Qianjin
Q
Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Wu
Ailing
A
Richardson
Bruce C
BC
D024506:5' Flanking Region / Q000187:drug effects; D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D053282:CD27 Ligand; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D011342:Procainamide / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
D015703:Antigens, CD; D053282:CD27 Ligand; C505771:CD70 protein, human; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; D006830:Hydralazine; D011342:Procainamide