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...

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Veröffentlicht in:Molecular and cellular biology 2015-07, Vol.35 (13), p.2332-2343
Hauptverfasser: Rauch, Isabella, Rosebrock, Felix, Hainzl, Eva, Heider, Susanne, Majoros, Andrea, Wienerroither, Sebastian, Strobl, Birgit, Stockinger, Silvia, Kenner, Lukas, Müller, Mathias, Decker, Thomas
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Sprache:eng
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Zusammenfassung: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.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.01498-14