title: IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo.
abstract: BACKGROUND
  The transcription factor IRF4 is involved in several T-cell-dependent chronic inflammatory diseases. To elucidate the mechanisms for pathological cytokine production in colitis, we addressed the role of the IRF transcription factors in human inflammatory bowel disease (IBD) and experimental colitis.
  
  
  METHODS
  IRF levels and cytokine production in IBD patients were studied as well as the effects of IRF4 deficiency in experimental colitis.
  
  
  RESULTS
  In contrast to IRF1, IRF5, and IRF8, IRF4 expression in IBD was augmented in the presence of active inflammation. Furthermore, IRF4 levels significantly correlated with IL-6 and IL-17 mRNA expression and to a lesser extent with IL-22 mRNA expression in IBD. To further explore the role of IRF4 under in vivo conditions, we studied IRF4-deficient and wildtype mice in experimental colitis. In contrast to DSS colitis, IRF4 deficiency was protective in T-cell-dependent transfer colitis associated with reduced RORα/γt levels and impaired IL-6, IL-17a, and IL-22 production, suggesting that IRF4 acts as a master regulator of mucosal Th17 cell differentiation. Subsequent mechanistic studies using database analysis, chromatin immunoprecipitation, and electrophoretic mobility shift assays identified a novel IRF4 binding site in the IL-17 gene promoter. Overexpression of IRF4 using retroviral infection induced IL-17 production and IL-17 together with IL-6 induced RORγt expression.
  
  
  CONCLUSIONS
  IRF4 can directly bind to the IL-17 promotor and induces mucosal RORγt levels and IL-17 gene expression thereby controlling Th17-dependent colitis. Targeting of this molecular mechanism may lead to novel therapeutic approaches in human IBD.
authors.affiliation: 1st Medical Clinic, University of Erlangen, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Mudter
authors.forename: Jingling
authors.initials: J
authors.lastname: Yu
authors.forename: Christel
authors.initials: C
authors.lastname: Zufferey
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Benno
authors.initials: B
authors.lastname: Weigmann
authors.forename: Arthur
authors.initials: A
authors.lastname: Hoffman
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schenk
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Hans A
authors.initials: HA
authors.lastname: Lehr
authors.forename: Christoph
authors.initials: C
authors.lastname: Mueller
authors.forename: Michael
authors.initials: M
authors.lastname: Lohoff
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000328:Adult; D000818:Animals; D003092:Colitis / Q000235:genetics* / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D058504:Th17 Cells / Q000378:metabolism* / Q000502:physiology; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D015850:Interleukin-6; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000099218:Interferon Regulatory Factor-4; C508717:IL17A protein, human; C539900:RORC protein, human