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  • 1
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    Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-01-11
    Description: Half a century ago, chronic granulomatous disease (CGD) was first described as a disease fatally affecting the ability of children to survive infections. Various milestone discoveries have since been made, from an insufficient ability of patients' leucocytes to kill microbes to the underlying genetic abnormalities. In this inherited disorder, phagocytes lack NADPH oxidase activity and do not generate reactive oxygen species, most notably superoxide anion, causing recurrent bacterial and fungal infections. Patients with CGD also suffer from chronic inflammatory conditions, most prominently granuloma formation in hollow viscera. The precise mechanisms of the increased microbial pathogenicity have been unclear, and more so the reasons for the exaggerated inflammatory response. Here we show that a superoxide-dependent step in tryptophan metabolism along the kynurenine pathway is blocked in CGD mice with lethal pulmonary aspergillosis, leading to unrestrained Vgamma1(+) gammadelta T-cell reactivity, dominant production of interleukin (IL)-17, defective regulatory T-cell activity and acute inflammatory lung injury. Although beneficial effects are induced by IL-17 neutralization or gammadelta T-cell contraction, complete cure and reversal of the hyperinflammatory phenotype are achieved by replacement therapy with a natural kynurenine distal to the blockade in the pathway. Effective therapy, which includes co-administration of recombinant interferon-gamma (IFN-gamma), restores production of downstream immunoactive metabolites and enables the emergence of regulatory Vgamma4(+) gammadelta and Foxp3(+) alphabeta T cells. Therefore, paradoxically, the lack of reactive oxygen species contributes to the hyperinflammatory phenotype associated with NADPH oxidase deficiencies, through a dysfunctional kynurenine pathway of tryptophan catabolism. Yet, this condition can be reverted by reactivating the pathway downstream of the superoxide-dependent step.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Romani, Luigina -- Fallarino, Francesca -- De Luca, Antonella -- Montagnoli, Claudia -- D'Angelo, Carmen -- Zelante, Teresa -- Vacca, Carmine -- Bistoni, Francesco -- Fioretti, Maria C -- Grohmann, Ursula -- Segal, Brahm H -- Puccetti, Paolo -- England -- Nature. 2008 Jan 10;451(7175):211-5. doi: 10.1038/nature06471.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy. lromani@unipg.it〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18185592" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aspergillosis/complications/immunology/microbiology/pathology ; Aspergillus fumigatus/physiology ; Chronic Disease ; Disease Models, Animal ; Granulomatous Disease, Chronic/complications/drug therapy/*metabolism/*pathology ; Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics/metabolism ; Inflammation/complications/drug therapy/*metabolism/pathology ; Interferon-gamma/immunology/therapeutic use ; Interleukin-17/deficiency/metabolism ; Kynurenine/*metabolism/therapeutic use ; Lung/immunology/pathology ; Lung Diseases, Fungal/complications/immunology/microbiology/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidase/deficiency/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Antigen, T-Cell, gamma-delta/immunology ; Superoxides/metabolism ; T-Lymphocytes/enzymology/immunology/pathology ; Tryptophan/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Aryl hydrocarbon receptor control of a disease tolerance defence pathway (2014)
    Nature Publishing Group (NPG)
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    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
    Published by Nature Publishing Group (NPG)
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  • 3
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    NFATc2 mediates epigenetic modification of dendritic cell cytokine and chemokine responses to dectin-1 stimulation (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-24
    Description: The transcription factor NFATc2 regulates dendritic cell (DC) responses to microbial stimulation through the C-type lectin receptor dectin-1. But the genetic targets of NFATc2 and their effects on DC function remain largely unknown. Therefore we used ChIP-seq to conduct genome-wide mapping of NFATc2 target sites in dectin-1-activated DCs. By combining binding-site data with a comprehensive gene expression profile, we found that NFATc2 occupancy regulates the expression of a subset of dectin-1-activated genes. Surprisingly, NFATc2 targeted an extensive range of DC-derived cytokines and chemokines, including regulatory cytokines such as IL2, IL23a and IL12b. Furthermore, we demonstrated that NFATc2 binding is required to induce the histone 3 lysine 4 trimethylation (H3K4me3) epigenetic mark, which is associated with enhanced gene expression. Together, these data show that the transcription factor NFATc2 mediates epigenetic modification of DC cytokine and chemokine genes leading to activation of their expression.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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