IRF4 selectively controls cytokine gene expression in chronic intestinal inflammation.
The authors previously showed that interferon regulatory factor (IRF)4 knockout mice are protected from experimental oxazolone and TNBS colitis. Here the effect of IRF4 on the expression of pro- and anti-inflammatory cytokines in TNBS colitis and long-term CD45RB(high) transfer colitis is examined. In TNBS colitis, no differences were found in interleukin (IL)-18 and tumor necrosis factor (TNF)-alpha expression between IRF4 knockout and wild-type mice. However, significant differences were detected in IL-6 and IL-17 production. Upon treatment with hyper-IL-6, IRF4(-/-) mice lost their protective properties towards TNBS application. Hyper-IL-6 application induced IL-6 mRNA, but not IL-17 mRNA expression, suggesting that IL-6 deficiency is not primarily responsible for the lack of IL-17 production. T-bet and GATA-3 mRNA expressions were not affected upon IL-6 application. In transfer colitis, colonic cytokine mRNA analysis revealed a reduced production of IL-6 in IRF4(-/-) reconstituted mice in the long-term course. In contrast, several other cytokines did not differ between the two groups (e.g. TNF-alpha and IL-10). Measurement of supernatants from splenic mononuclear cells revealed a significant difference in IL-6 and IL-17 production between the two groups. These findings suggest that IRF4 selectively regulates cytokine gene expression in chronic inflammation. IRF4 therefore emerges as an attractive target for the therapy of chronic intestinal inflammation. Blocking IRF4 might be an interesting option to modulate inflammation in the advanced state of inflammation.
Mudter
Jonas
J
1st Medical Clinic, University of Erlangen-Nürnberg, D-91054, Erlangen, Germany.
Yu
Jingling
J
Amoussina
Lioubov
L
Weigmann
Benno
B
Hoffman
Arthur
A
Rücknagel
Katrin
K
Galle
Peter R
PR
Neurath
Markus F
MF
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D000099218:Interferon Regulatory Factor-4
D016207:Cytokines; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D015850:Interleukin-6; D014302:Trinitrobenzenesulfonic Acid; D000099218:Interferon Regulatory Factor-4; C499308:Rag2 protein, mouse