期刊
NATURE
卷 511, 期 7508, 页码 184-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13323
关键词
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资金
- Italian Association for Cancer Research (AIRC)
- Fondazione Italiana Sclerosi Multipla [2010/R/17]
- Associazione Umbra Contro il Cancro
- Bayer Grants4Target Focus [2012-03-0630]
- Bayer Early Career Investigator Award from the US National Institutes of Environmental Health Sciences [R01ES007685]
- Specific Targeted Research Project FUNMETA
- Regione dell'Umbria [GR-2008-1138004]
- Italian Ministry of Health
- Grants-in-Aid for Scientific Research [23590362] Funding Source: KAKEN
Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to down-regulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. There sulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhRin contributing to host fitness.
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