The transcription factor IFN regulatory factor–4 controls experimental colitis in mice via T cell–derived IL-6
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
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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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 7

Hyper–IL-6 treatment induces IL-6 but not TNF production in IRF4–/– mice.

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Hyper–IL-6 treatment induces IL-6 but not TNF production in IRF4–/– mice...
(A) WT and IRF4-knockout mice were treated with TNBS, and some mice received hyper–IL-6. Relative expression levels of IL-6, TNF, and TGF-β mRNA were measured by quantitative real-time RT-PCR on day 4. Values were normalized to β-actin expression levels. TNBS-treated IRF4–/– mice (n = 8) showed low mucosal expression of IL-6 mRNA. Hyper–IL-6 application induced a 14-fold increase of IL-6 production in TNBS-treated IRF4–/– mice (n = 6) (**P < 0.01). The expression levels of the proinflammatory cytokine TNF as well as levels of TGF-β remained unaffected, however. Treatment of WT mice with hyper–IL-6 (n = 5; WT mice, n = 4) did not lead to a further significant increase of IL-6, TNF, or TGF-β. Data are shown as mean values ± SEM from 3 experiments. (B and C) IRF4-knockout mice and WT mice were treated with TNBS, and the presence of apoptosis in gut mononuclear cells was determined by propidium iodide and annexin V staining using FACS analysis (n = 6 per group). IRF4-deficient mononuclear cells in the gut showed a significantly higher presence of cell apoptosis in TNBS colitis than in WT cells, and this could be abrogated by hyper–IL-6 administration. One representative experiment is shown. *P < 0.05. (D) Apoptosis of gut mononuclear cells was determined by TUNEL assays. Hyper–IL-6 treatment prevented the induction of mononuclear cell apoptosis in the colon of IRF4-deficient mice. One representative experiment is shown (n = 4 per group). Original magnification, ×300.