Titre
IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Mudter, J.
Auteure/Auteur
Yu, J.
Auteure/Auteur
Zufferey, C.
Auteure/Auteur
Brüstle, A.
Auteure/Auteur
Wirtz, S.
Auteure/Auteur
Weigmann, B.
Auteure/Auteur
Hoffman, A.
Auteure/Auteur
Schenk, M.
Auteure/Auteur
Galle, P.R.
Auteure/Auteur
Lehr, H.A.
Auteure/Auteur
Mueller, C.
Auteure/Auteur
Lohoff, M.
Auteure/Auteur
Neurath, M.F.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1536-4844
Statut éditorial
Publié
Date de publication
2011
Volume
17
Numéro
6
Première page
1343
Dernière page/numéro d’article
1358
Langue
anglais
Résumé
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 ROR alpha/gamma t 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 ROR gamma t expression.Conclusions: IRF4 can directly bind to the IL-17 promotor and induces mucosal ROR gamma t 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.
PID Serval
serval:BIB_13A22B3E6D75
PMID
Date de création
2011-05-30T08:56:49.218Z
Date de création dans IRIS
2025-05-20T16:41:53Z