Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against a host of nuclear antigens. The pathogenesis of lupus is incompletely understood. Environmental factors may play a role via altering DNA methylation, a mechanism regulating gene expression. In lupus, genes including CD11a and CD70 are overexpressed in T cells as a result of promoter hypomethylation. T-cell DNA methyltransferase expression is regulated in part by the extracellular signal-regulated kinase (ERK) signaling pathway. In this study, we investigate the effects of decreased ERK pathway signaling in T cells using transgenic animals. We generated a transgenic mouse that inducibly expresses a dominant-negative MEK in T cells in the presence of doxycycline. We show that decreased ERK pathway signaling in T cells results in decreased expression of DNA methyltransferase 1 and overexpression of the methylation-sensitive genes CD11a and CD70, similar to T cells in human lupus. Our transgenic animal model also develops anti-dsDNA antibodies. Interestingly, microarray expression assays revealed overexpression of several interferon-regulated genes in the spleen similar to peripheral blood cells of lupus patients. This model supports the contention that ERK pathway signaling defects in T cells contribute to the development of autoimmunity.
US Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA. amr-sawalha@omrf.ouhsc.edu
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Sawalha
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M
Jeffries
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R
Webb
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Lu
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Gorelik
D
D
Ray
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Osban
N
N
Knowlton
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Johnson
B
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Richardson
D000818:Animals; D040881:CD11a Antigen / Q000235:genetics / Q000378:metabolism; D053282:CD27 Ligand / Q000235:genetics / Q000378:metabolism; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000276:immunology*; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism
D040881:CD11a Antigen; D053282:CD27 Ligand; C485852:Dmap1 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D007372:Interferons; D008780:Methyltransferases; D048049:Extracellular Signal-Regulated MAP Kinases; D004318:Doxycycline