Noncanonical Effects of IRF9 in Intestinal Inflammation: More than Type I and Type III Interferons.
The interferon (IFN)-stimulated gene factor 3 (ISGF3) transcription factor with its Stat1, Stat2, and interferon regulatory factor 9 (IRF9) subunits is employed for transcriptional responses downstream of receptors for type I interferons (IFN-I) that include IFN-α and IFN-β and type III interferons (IFN-III), also called IFN-λ. Here, we show in a murine model of dextran sodium sulfate (DSS)-induced colitis that IRF9 deficiency protects animals, whereas the combined loss of IFN-I and IFN-III receptors worsens their condition. We explain the different phenotypes by demonstrating a function of IRF9 in a noncanonical transcriptional complex with Stat1, apart from IFN-I and IFN-III signaling. Together, Stat1 and IRF9 produce a proinflammatory activity that overrides the benefits of the IFN-III response on intestinal epithelial cells. Our results further suggest that the CXCL10 chemokine gene is an important mediator of this proinflammatory activity. We thus establish IFN-λ as a potentially anticolitogenic cytokine and propose an important role for IRF9 as a component of noncanonical Stat complexes in the development of colitis.
Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Isabella
I
Rauch
Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Felix
F
Rosebrock
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Eva
E
Hainzl
Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Vienna, Austria.
Susanne
S
Heider
Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Andrea
A
Majoros
Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Sebastian
S
Wienerroither
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Birgit
B
Strobl
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Silvia
S
Stockinger
Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Vienna, Austria.
Lukas
L
Kenner
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Mathias
M
Müller
Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria Thomas.decker@univie.ac.at.
Thomas
T
Decker
D000818:Animals; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D017353:Gene Deletion; D005786:Gene Expression Regulation; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics* / Q000276:immunology*; D007372:Interferons / Q000276:immunology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology; D015398:Signal Transduction
D054357:Chemokine CXCL10; D016264:Dextran Sulfate; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007372:Interferons; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C494228:Isgf3g protein, mouse