Document Detail


Structural determination and Toll-like receptor 2-dependent proinflammatory activity of dimycolyl-diarabino-glycerol from Mycobacterium marinum.
MedLine Citation:
PMID:  22798072     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Although it was identified in the cell wall of several pathogenic mycobacteria, the biological properties of dimycolyl-diarabino-glycerol have not been documented yet. In this study an apolar glycolipid, presumably corresponding to dimycolyl-diarabino-glycerol, was purified from Mycobacterium marinum and subsequently identified as a 5-O-mycolyl-β-Araf-(1→2)-5-O-mycolyl-α-Araf-(1→1')-glycerol (designated Mma_DMAG) using a combination of nuclear magnetic resonance spectroscopy and mass spectrometry analyses. Lipid composition analysis revealed that mycolic acids were dominated by oxygenated mycolates over α-mycolates and devoid of trans-cyclopropane functions. Highly purified Mma_DMAG was used to demonstrate its immunomodulatory activity. Mma_DMAG was found to induce the secretion of proinflammatory cytokines (TNF-α, IL-8, IL-1β) in human macrophage THP-1 cells and to trigger the expression of ICAM-1 and CD40 cell surface antigens. This activation mechanism was dependent on TLR2, but not on TLR4, as demonstrated by (i) the use of neutralizing anti-TLR2 and -TLR4 antibodies and by (ii) the detection of secreted alkaline phosphatase in HEK293 cells co-transfected with the human TLR2 and secreted embryonic alkaline phosphatase reporter genes. In addition, transcriptomic analyses indicated that various genes encoding proinflammatory factors were up-regulated after exposure of THP-1 cells to Mma_DMAG. Importantly, a wealth of other regulated genes related to immune and inflammatory responses, including chemokines/cytokines and their respective receptors, adhesion molecules, and metalloproteinases, were found to be modulated by Mma_DMAG. Overall, this study suggests that DMAG may be an active cell wall glycoconjugate driving host-pathogen interactions and participating in the immunopathogenesis of mycobacterial infections.
Authors:
Elisabeth Elass-Rochard; Yoann Rombouts; Bernadette Coddeville; Emmanuel Maes; Renaud Blervaque; David Hot; Laurent Kremer; Yann Guérardel
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-13
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-08     Completed Date:  2012-12-31     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  34432-44     Citation Subset:  IM    
Affiliation:
Université Lille Nord de France, Université Lille1, Unité de Glycobiologie Structurale et Fonctionnelle, UGSF, IFR 147, France. elisabeth.elass@univ-lille1.fr
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MeSH Terms
Descriptor/Qualifier:
Antigens, CD40 / immunology,  metabolism
Cytokines* / immunology,  secretion
Glycolipids* / chemistry,  immunology,  isolation & purification,  metabolism,  pharmacology
HEK293 Cells
Host-Pathogen Interactions
Humans
Inflammation Mediators* / immunology,  metabolism
Intercellular Adhesion Molecule-1 / immunology,  metabolism
Macrophages* / immunology,  metabolism
Mycobacterium Infections, Nontuberculous / immunology,  metabolism
Mycobacterium marinum* / chemistry,  immunology,  metabolism
Toll-Like Receptor 2* / immunology,  metabolism
Chemical
Reg. No./Substance:
0/Antigens, CD40; 0/Cytokines; 0/Glycolipids; 0/ICAM1 protein, human; 0/Inflammation Mediators; 0/TLR2 protein, human; 0/Toll-Like Receptor 2; 126547-89-5/Intercellular Adhesion Molecule-1
Comments/Corrections

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