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 5

Decreased activation of the antiapoptotic IL-6 pathway in IRF4-deficient T cells.

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Decreased activation of the antiapoptotic IL-6 pathway in IRF4-deficient...
(A) LPMCs from WT and IRF4-deficient mice were cultured with or without anti-CD3/CD28 antibodies. IL-6 production was higher in WT mice as compared with IRF4-deficient mice upon costimulation. (B–D) T cell–enriched LPMCs (B), CD90+ LP T cells (C), or splenic T cells (D) were isolated from TNBS-treated mice and stimulated for 2 days. LP cells but not spleen cells from TNBS-treated IRF4-deficient mice produced significantly lower amounts of IL-6 than cells from TNBS-treated WT mice (n = 9–10 mice per group; **P < 0.01) (E) TNBS-treated WT mice exhibited an increased number of IL-6–positive cells (red) in the lamina propria as compared with controls. Original magnification, ×300. (F) IL-6–positive cells were counted in TNBS-treated IRF4–/– and WT mice (5 HPFs). IL-6–positive cells were increased in TNBS-treated WT mice compared with IRF4-deficient mice. (G) Colonic cryosections were stained using TUNEL assays. There were more positive cells in the colons of TNBS-treated IRF4-knockout mice than in TNBS-treated WT mice (n = 6 per group). Positive and negative control samples are shown. Original magnification, ×300. (H) Lamina propria cells were isolated from either TNBS-treated WT or IRF4–/– mice (n = 6 per group) and stained for CD3 and annexin V. Lamina propria cells from IRF4–/– mice showed more annexin V and CD3 double-positive cells than those from WT mice (15% versus 3%). No such differences were detected in spleen cells (8% versus 11%).