The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6.
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.
1st Medical Clinic, University of Mainz, Mainz, Germany.
Jonas
J
Mudter
Lioubov
L
Amoussina
Mirjam
M
Schenk
Jingling
J
Yu
Anne
A
Brüstle
Benno
B
Weigmann
Raja
R
Atreya
Stefan
S
Wirtz
Christoph
C
Becker
Arthur
A
Hoffman
Imke
I
Atreya
Stefan
S
Biesterfeld
Peter R
PR
Galle
Hans A
HA
Lehr
Stefan
S
Rose-John
Christoph
C
Mueller
Michael
M
Lohoff
Markus F
MF
Neurath
D019264:Adoptive Transfer; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010081:Oxazolone / Q000494:pharmacology; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D000099218:Interferon Regulatory Factor-4
D016207:Cytokines; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D015850:Interleukin-6; D010081:Oxazolone; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D014302:Trinitrobenzenesulfonic Acid; D000099218:Interferon Regulatory Factor-4; C499308:Rag2 protein, mouse; C104543:interleukin 6-interleukin 6 receptor fusion protein, recombinant