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Mol Cell Biol. 2015 Jul;35(13):2332-43. doi: 10.1128/MCB.01498-14. Epub 2015 Apr 27.

Noncanonical Effects of IRF9 in Intestinal Inflammation: More than Type I and Type III Interferons.

Author information

1
Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
2
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
3
Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Vienna, Austria.
4
Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria Thomas.decker@univie.ac.at.

Abstract

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.

PMID:
25918247
PMCID:
PMC4456449
DOI:
10.1128/MCB.01498-14
[Indexed for MEDLINE]
Free PMC Article

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