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

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.

• Authors: Isabella Rauch, Felix Rosebrock, Eva Hainzl, Susanne Heider, Andrea Majoros, Sebastian Wienerroither, Birgit Strobl, Silvia Stockinger, Lukas Kenner, Mathias Müller, Thomas Decker
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 13 Pg. 2332-43 (Jul 2015) ISSN: 1098-5549 [Electronic] United States
• PMID: 25918247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Chemokine CXCL10
• IRF9 protein, mouse
• Interferon-Stimulated Gene Factor 3, gamma Subunit
• Receptors, Interferon
• STAT1 Transcription Factor
• Stat1 protein, mouse
• Interferons
• Dextran Sulfate

Topics

• Animals
• Cells, Cultured
• Chemokine CXCL10 (genetics, immunology)
• Colitis (chemically induced, genetics, immunology, pathology)
• Colon (immunology, pathology)
• Dextran Sulfate
• Gene Deletion
• Gene Expression Regulation
• Interferon-Stimulated Gene Factor 3, gamma Subunit (genetics, immunology)
• Interferons (immunology)
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Promoter Regions, Genetic
• Receptors, Interferon (genetics, immunology)
• STAT1 Transcription Factor (immunology)
• Signal Transduction