期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 35, 期 13, 页码 2332-2343出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01498-14
关键词
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资金
- Austrian Science Fund (FWF) [SFB-F28, P25186-B22, P26011]
- Austrian Federal Ministry of Science and Research through GEN-AU III (project InflammoBiota)
- Austrian Science Fund (FWF) [P25186, P26011] Funding Source: Austrian Science Fund (FWF)
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-alpha and IFN-beta and type III interferons (IFN-III), also called IFN-lambda. 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-lambda as a potentially anticolitogenic cytokine and propose an important role for IRF9 as a component of noncanonical Stat complexes in the development of colitis.
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