Publication Date:
2014-06-17
Description:
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 downregulate 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. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bessede, Alban -- Gargaro, Marco -- Pallotta, Maria T -- Matino, Davide -- Servillo, Giuseppe -- Brunacci, Cinzia -- Bicciato, Silvio -- Mazza, Emilia M C -- Macchiarulo, Antonio -- Vacca, Carmine -- Iannitti, Rossana -- Tissi, Luciana -- Volpi, Claudia -- Belladonna, Maria L -- Orabona, Ciriana -- Bianchi, Roberta -- Lanz, Tobias V -- Platten, Michael -- Della Fazia, Maria A -- Piobbico, Danilo -- Zelante, Teresa -- Funakoshi, Hiroshi -- Nakamura, Toshikazu -- Gilot, David -- Denison, Michael S -- Guillemin, Gilles J -- DuHadaway, James B -- Prendergast, George C -- Metz, Richard -- Geffard, Michel -- Boon, Louis -- Pirro, Matteo -- Iorio, Alfonso -- Veyret, Bernard -- Romani, Luigina -- Grohmann, Ursula -- Fallarino, Francesca -- Puccetti, Paolo -- P30 CA056036/CA/NCI NIH HHS/ -- R01 CA109542/CA/NCI NIH HHS/ -- R01 ES007685/ES/NIEHS NIH HHS/ -- R01ES007685/ES/NIEHS NIH HHS/ -- England -- Nature. 2014 Jul 10;511(7508):184-90. doi: 10.1038/nature13323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2] IMS Laboratory, University of Bordeaux, 33607 Pessac, France [3]. ; 1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2]. ; Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. ; Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy. ; Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy. ; 1] Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany [2] Department of Neurooncology, University Hospital, 69120 Heidelberg, Germany. ; Center for Advanced Research and Education, Asahikawa Medical University, 078-8510 Asahikawa, Japan. ; Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 565-0871 Osaka, Japan. ; CNRS UMR6290, Institut de Genetique et Developpement de Rennes, Universite de Rennes 1, 35043 Rennes, France. ; Department of Environmental Toxicology, University of California, Davis, 95616 California, USA. ; Australian School of Advanced Medicine (ASAM), Macquarie University, 2109 New South Wales, Australia. ; Lankenau Institute for Medical Research, Wynnewood, 19096 Pennsylvania, USA. ; New Link Genetics Corporation, Ames, 50010 Iowa, USA. ; IMS Laboratory, University of Bordeaux, 33607 Pessac, France. ; Bioceros, 3584 Utrecht, The Netherlands. ; Department of Medicine, University of Perugia, 06132 Perugia, Italy. ; Department of Clinical Epidemiology & Biostatistics, McMaster University, Ontario L8S 4K1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24930766" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bacterial Infections/immunology/metabolism
;
Disease Resistance/drug effects/*genetics/*immunology
;
Endotoxemia/genetics/immunology/metabolism
;
Enzyme Activation/drug effects
;
Gene Expression Regulation/drug effects
;
Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
;
Inflammation/enzymology/genetics/metabolism
;
Kynurenine/metabolism
;
Lipopolysaccharides/pharmacology
;
Mice
;
Phosphorylation
;
Receptors, Aryl Hydrocarbon/genetics/*metabolism
;
Signal Transduction
;
Tryptophan Oxygenase/metabolism
;
src-Family Kinases/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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