title: T cell PKCδ kinase inactivation induces lupus-like autoimmunity in mice.
abstract: Genetic and environmental factors contribute to the onset and progression of lupus. CD4+ T cells from patients with active lupus show a decreased ERK signaling pathway, which causes changes in gene expression. The defect points to its upstream regulator, PKCδ, which exhibits a deficient activity due to oxidative stress. Our aim was to investigate the effect of a defective PKCδ in the development of lupus. We generated a double transgenic C57BL6 × SJL mouse that expresses a doxycycline-induced dominant negative PKCδ (dnPKCδ) in T cells. The transgenic mice displayed decreased T cell ERK signaling, decreased DNMT1 expression and overexpression of methylation sensitive genes involved in the exaggerated immune response in the pathogenesis of lupus. The mice developed anti-dsDNA autoantibodies and glomerulonephritis with IgG deposition. The study indicates common pathogenic mechanisms with human lupus, suggesting that environmentally-mediated T cell PKCδ inactivation plays a causative role in lupus.
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: ggorelik@umich.edu.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Gorelik
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Dipak
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI, USA; Ann Arbor VA Medical Center, Ann Arbor, MI, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Richardson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001323:Autoantibodies / Q000378:metabolism; D015551:Autoimmunity; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D005921:Glomerulonephritis / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000201:enzymology*; D015534:Trans-Activators
chemical_list: D000900:Anti-Bacterial Agents; D001323:Autoantibodies; D007074:Immunoglobulin G; D015534:Trans-Activators; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D004318:Doxycycline
keywords: Autoimmunity; Extracellular signal-regulated kinase (ERK); Lupus; PKCδ; T cells; Transgenic mouse model
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