Lipomannans, but not lipoarabinomannans, purified from Mycobacterium chelonae and Mycobacterium kansasii induce TNF-alpha and IL-8 secretion by a CD14-toll-like receptor 2-dependent mechanism.
Lipoarabinomannans (LAMs) are glycolipids from the mycobacterial cell wall that exhibit various biological activities, including proinflammatory and anti-inflammatory responses. However, little is known about the properties of lipomannans (LMs), considered to be precursors of LAMs. In this study, we provide evidence that LMs purified from Mycobacterium chelonae and a clinical strain of Mycobacterium kansasii stimulated mRNA expression and secretion of TNF-alpha and IL-8 from human macrophage-like differentiated THP-1 cells. In contrast to LMs, LAMs were not able to induce a significant cytokine-inducing effect. The mechanism of activation by LMs was investigated using various Abs raised against surface receptors for multiple bacterial products. The presence of anti-CD14 or anti-Toll-like receptor 2 (TLR2) Abs profoundly affected production of TNF-alpha and IL-8, suggesting that both CD14 and TLR2 participate in the LM-mediated activation process. Furthermore, stimulation of cells was dependent on the presence of the LPS-binding protein, a plasma protein that transfers glycolipids to CD14. Chemical degradation of the arabinan domain of mannose-capped LAM from M. kansasii, which presented no cytokine-eliciting effect, restored the cytokine-inducing activity at a level similar to those of LMs. These results support the hypothesis that the presence of an arabinan in LAMs prevents the interaction of these glycolipids with TLR2/CD14 receptors. In addition, we found that phosphatidylinositol dimannosides isolated from M. kansasii did not induce cytokine secretion. This study suggests that LMs isolated from different mycobacterial species participate in the immunomodulation of the infected host and that the D-mannan core of this glycolipid is essential for this function.
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Unité de Glycobiologie Structurale et Fonctionnelle, Unité Mixte de Recherche 8576 du Centre National de la Recherche Scientifique, Institut Fédératif de Recherche no. 118, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France.
Guérardel
Yann
Y
Kremer
Laurent
L
Masson
Maryse
M
Legrand
Dominique
D
Mazurier
Joël
J
Elass
Elisabeth
E
D000209:Acute-Phase Proteins; D002352:Carrier Proteins / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D016926:Mycobacterium chelonae / Q000276:immunology* / Q000472:pathogenicity; D019909:Mycobacterium kansasii / Q000276:immunology* / Q000472:pathogenicity; D010716:Phosphatidylinositols / Q000502:physiology; D011134:Polysaccharides / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000502:physiology*; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010716:Phosphatidylinositols; D011134:Polysaccharides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein; C495342:TLR2 protein, human; C050016:lipoarabinomannan; C064351:lipomannan; C054977:phosphatidylinositol dimannoside; C030080:araban