Noncanonical effects of IRF9 in intestinal inflammation: More than type I and type III interferons

Isabella Rauch, Felix Rosebrock, Eva Hainzl, Susanne Heider, Andrea Majoros, Sebastian Wienerroither, Birgit Strobl, Silvia Stockinger, Lukas Kenner, Mathias Müller, Thomas Decker

Research output: Contribution to journalArticle

27 Scopus citations

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-ß 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.

Original languageEnglish (US)
Pages (from-to)2332-2343
Number of pages12
JournalMolecular and cellular biology
Volume35
Issue number13
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Rauch, I., Rosebrock, F., Hainzl, E., Heider, S., Majoros, A., Wienerroither, S., Strobl, B., Stockinger, S., Kenner, L., Müller, M., & Decker, T. (2015). Noncanonical effects of IRF9 in intestinal inflammation: More than type I and type III interferons. Molecular and cellular biology, 35(13), 2332-2343. https://doi.org/10.1128/MCB.01498-14