| Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses. | |
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MedLine Citation:
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PMID: 20554962 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and has high expression in alternatively activated alveolar macrophages and macrophage-derived foam cells, both cell types relevant to tuberculosis pathogenesis. In this study, we show that virulent M. tuberculosis and its cell wall mannose-capped lipoarabinomannan induce PPARgamma expression through a macrophage mannose receptor-dependent pathway. When activated, PPARgamma promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPARgamma agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A(2) activation, which is required for PPARgamma ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-kappaB activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPARgamma and preferentially uses the NF-kappaB-mediated pathway to induce IL-8 production. Finally, PPARgamma knockdown in human macrophages enhances TNF production and controls the intracellular growth of M. tuberculosis. These data identify a new molecular pathway that links engagement of the mannose receptor, an important pattern recognition receptor for M. tuberculosis, with PPARgamma activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis. |
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Authors:
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Murugesan V S Rajaram; Michelle N Brooks; Jessica D Morris; Jordi B Torrelles; Abul K Azad; Larry S Schlesinger |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-06-16 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 185 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-05 Completed Date: 2010-08-10 Revised Date: 2011-07-20 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 929-42 Citation Subset: AIM; IM |
Affiliation:
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Center for Microbial Interface Biology, Ohio State University, Columbus, OH 43210, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anilides
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pharmacology Blotting, Western Cells, Cultured Cyclooxygenase 2 / metabolism Enzyme Activation / drug effects Host-Pathogen Interactions / immunology Humans Interleukin-8 / metabolism Lectins, C-Type / genetics, metabolism* Lipopolysaccharides / immunology, pharmacology Macrophages / cytology, metabolism*, microbiology Mannose-Binding Lectins / genetics, metabolism* Models, Immunological Mycobacterium tuberculosis / immunology*, physiology NF-kappa B / metabolism PPAR gamma / antagonists & inhibitors, genetics, metabolism* Phospholipases A2, Cytosolic / metabolism RNA Interference Receptors, Cell Surface / genetics, metabolism* Signal Transduction / drug effects, immunology Tumor Necrosis Factor-alpha / metabolism p38 Mitogen-Activated Protein Kinases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AI052458/AI/NIAID NIH HHS; AI059639/AI/NIAID NIH HHS; R01 AI052458-05/AI/NIAID NIH HHS; R01 AI059639-05/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/2-chloro-5-nitrobenzanilide; 0/Anilides; 0/Interleukin-8; 0/Lectins, C-Type; 0/Lipopolysaccharides; 0/Mannose-Binding Lectins; 0/NF-kappa B; 0/PPAR gamma; 0/Receptors, Cell Surface; 0/Tumor Necrosis Factor-alpha; 0/lipoarabinomannan; 0/mannose receptor; EC 1.14.99.1/Cyclooxygenase 2; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.1.1.4/Phospholipases A2, Cytosolic |
| Comments/Corrections | |
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