title: Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice.
abstract: OBJECTIVE
  Interferon regulatory factor 5 (IRF-5) is a transcription factor that mediates intracellular signals activated by engagement of Toll-like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus.
  
  
  METHODS
  We crossed gene-targeted IRF5-deficient (IRF5(-/-) ) mice with MRL/MpJ-lpr/lpr (MRL/lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function.
  
  
  RESULTS
  IRF5(-/-) MRL/lpr mice survived longer than control IRF5(+/+) MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLE-related nuclear antigens were lower in IRF5(-/-) MRL/lpr mouse serum, and numbers of activated CD4+ T cells were reduced in the spleen. Splenic DCs from IRF5(-/-) MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR-7 or TLR-9 ligands or immune complexes. Interferon-α production in response to CpG was also decreased.
  
  
  CONCLUSIONS
  Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients.
authors.affiliation: Department of Rheumatology, Faculty of Medicine, Saga University, Saga, Japan. taday@cc.saga-u.ac.jp
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Tada
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Aoki
authors.forename: Syuichi
authors.initials: S
authors.lastname: Koarada
authors.forename: Hisako
authors.initials: H
authors.lastname: Inoue
authors.forename: Rie
authors.initials: R
authors.lastname: Suematsu
authors.forename: Akihide
authors.initials: A
authors.lastname: Ohta
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Kohei
authors.initials: K
authors.lastname: Nagasawa
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000401:mortality; D006720:Homozygote; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D012307:Risk Factors; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9