The transcription factor IFN regulatory factor–4 controls experimental colitis in mice via T cell–derived IL-6
Jonas Mudter, … , Michael Lohoff, Markus F. Neurath
Jonas Mudter, … , Michael Lohoff, Markus F. Neurath
Published June 5, 2008
Citation Information: J Clin Invest. 2008;118(7):2415-2426. https://doi.org/10.1172/JCI33227.
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Research Article Gastroenterology

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

Abstract

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+CD45RBhi 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.

Authors

Jonas Mudter, Lioubov Amoussina, Mirjam Schenk, Jingling Yu, Anne Brüstle, Benno Weigmann, Raja Atreya, Stefan Wirtz, Christoph Becker, Arthur Hoffman, Imke Atreya, Stefan Biesterfeld, Peter R. Galle, Hans A. Lehr, Stefan Rose-John, Christoph Mueller, Michael Lohoff, Markus F. Neurath

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Figure 2

Abrogation of oxazolone-induced colitis in IRF4-deficient mice.

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Abrogation of oxazolone-induced colitis in IRF4-deficient mice. (A) IRF4...
(A) IRF4 expression was analyzed by immunofluorescence (red) in oxazolone colitis. IRF4–/– mice served as negative control (upper panel). Colitic WT mice had many IRF4-positive cells in the lamina propria (lower panel) as compared with untreated WT mice (middle panel). Original magnification, ×400. *P < 0.05. (B) WT (n = 8) and IRF4-deficient mice (n = 11) were treated by rectal administration of oxazolone following prior sensitization. WT (IRF4+/+) mice lost significantly more weight as compared with oxazolone-treated IRF4–/– mice, untreated WT mice (n = 5), or untreated knockout mice (n = 3). **P < 0.01 on days 3 and 4. (C) IRF4-deficient mice showed a significantly reduced endoscopic score. (D) Representative endoscopic pictures from each group are shown. (E) Histological scoring revealed a significantly higher degree of inflammation in oxazolone-treated WT mice as compared with IRF4–/– mice. Data are given as mean values ± SEM (IRF4+/+ plus oxazolone, n = 8; IRF4–/– plus oxazolone, n = 11; IRF4+/+, n = 5; IRF4–/–, n = 3). (F) Histological findings showed moderate to severe inflammation in WT mice, whereas little or no inflammation was noted in IRF4–/– mice. (G) In further studies, chronic oxazolone colitis was evaluated. Mice were treated 3 times by intrarectal application of oxazolone and evaluated on day 21. A more severe colitis activity was induced in WT mice (n = 5) as compared with IRF4–/– mice (n = 5) (F). This was underlined by differences (**P < 0.01) in the histologic score between both groups (G). (H) Representative histologic pictures from each group are shown. Original magnification, ×100.