The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6.

Détails

Ressource 1Télécharger: IPA18535667.pdf (1568.19 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_54B1BAA6F1FE
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6.
Périodique
Journal of Clinical Investigation
Auteur⸱e⸱s
Mudter J., Amoussina L., Schenk M., Yu J., Brüstle A., Weigmann B., Atreya R., Wirtz S., Becker C., Hoffman A., Atreya I., Biesterfeld S., Galle P.R., Lehr H.A., Rose-John S., Mueller C., Lohoff M., Neurath M.F.
ISSN
0021-9738
Statut éditorial
Publié
Date de publication
2008
Peer-reviewed
Oui
Volume
118
Numéro
7
Pages
2415-2426
Langue
anglais
Résumé
The proinflammatory cytokine IL-6 seems to have an important role in the intestinal inflammation that characterizes inflammatory bowel diseases (IBDs) such as Crohn disease and ulcerative colitis. However, little is known about the molecular mechanisms regulating IL-6 production in IBD. Here, we assessed the role of the transcriptional regulator IFN regulatory factor-4 (IRF4) in this process. Patients with either Crohn disease or ulcerative colitis exhibited increased IRF4 expression in lamina propria CD3+ T cells as compared with control patients. Consistent with IRF4 having a regulatory function in T cells, in a mouse model of IBD whereby colitis is induced in RAG-deficient mice by transplantation with CD4+CD45RB(hi) T cells, adoptive transfer of wild-type but not IRF4-deficient T cells resulted in severe colitis. Furthermore, IRF4-deficient mice were protected from T cell-dependent chronic intestinal inflammation in trinitrobenzene sulfonic acid- and oxazolone-induced colitis. In addition, IRF4-deficient mice with induced colitis had reduced mucosal IL-6 production, and IRF4 was required for IL-6 production by mucosal CD90+ T cells, which it protected from apoptosis. Finally, the protective effect of IRF4 deficiency could be abrogated by systemic administration of either recombinant IL-6 or a combination of soluble IL-6 receptor (sIL-6R) plus IL-6 (hyper-IL-6). Taken together, our data identify IRF4 as a key regulator of mucosal IL-6 production in T cell-dependent experimental colitis and suggest that IRF4 might provide a therapeutic target for IBDs.
Mots-clé
Adoptive Transfer, Adult, Animals, Apoptosis, CD4-Positive T-Lymphocytes, Colitis, Cytokines, DNA-Binding Proteins, Female, Gene Expression Regulation, Humans, Inflammatory Bowel Diseases, Interferon Regulatory Factors, Interleukin-6, Intestinal Mucosa, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Oxazolone, Receptors, Interleukin-6, Recombinant Fusion Proteins, T-Lymphocytes, Trinitrobenzenesulfonic Acid
Pubmed
Web of science
Open Access
Oui
Création de la notice
11/07/2008 11:19
Dernière modification de la notice
20/08/2019 14:09
Données d'usage