Phosphatidylinositol mannosides: Synthesis and suppression of allergic airway disease

Ainge, Gary D.; Hudson, Jennifer E.; Larsen, David S.; Painter, Gavin F.; Gill, Gurmit S.; Harper, Jacquie L.

doi:10.1016/j.bmc.2006.04.037

Cited by 37 publications

(58 citation statements)

References 32 publications

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“…Furthermore, PIMs have been reported to suppress allergic airway disease, which is associated with increased production of IL-10 (2, 63). However, PIM 1 and PIM 2 were used in the latter two studies (2,63) and IL-10 induction in this case likely involves a different pathway (22). In our experiments, in which LPS-primed MoDCs were cocultured with wild-type M. bovis BCG or the ⌬pimE and ⌬pimE ⌬capA mutant strains, no decrease in IL-10 secretion by MoDCs incubated with the mutant strains compared to wild-type M. bovis BCG was found (Fig.…”

Section: Discussionmentioning

confidence: 62%

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Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

et al. 2009

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The C-type lectin dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is the major receptor on DCs for mycobacteria of the Mycobacterium tuberculosis complex. Recently, we have shown that although the mannose caps of the mycobacterial surface glycolipid lipoarabinomannan (ManLAM) are essential for the binding to DC-SIGN, genetic removal of these caps did not diminish the interaction of whole mycobacteria with DC-SIGN and DCs. Here we investigated the role of the structurally related glycolipids phosphatidylinositol mannosides (PIMs) as possible ligands for DC-SIGN. In a binding assay with both synthetic and natural PIMs, DC-SIGN exhibited a high affinity for hexamannosylated PIM 6 , which contains terminal ␣(132)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di-and tetramannosylated PIM 2 and PIM 4 , respectively. To determine the role of PIM 6 in the binding of whole mycobacteria to DC-SIGN, a mutant strain of M. bovis bacillus Calmette-Guérin deficient in the production of PIM 6 (⌬pimE) was created, as well as a double knockout deficient in the production of both PIM 6 and the mannose caps on LAM (⌬pimE ⌬capA). Compared to the wild-type strain, both mutant strains bound similarly well to DC-SIGN and DCs. Furthermore, the wild-type and mutant strains induced comparable levels of interleukin-10 and interleukin-12p40 when used to stimulate DCs. Hence, we conclude that, like ManLAM, PIM 6 represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs.

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Section: Discussionmentioning

confidence: 62%

“…1). The number of mannosyl residues can range from one to six, as is denoted by the subscript to PIM (PIM 1 to PIM 6 ), with tri-and tetraacylated PIM 2 and PIM 6 as the predominant species (48). LAM and PIMs share the initial steps of their biosynthesis (40), with PIM 4 as the assumed branching point (11,43).…”

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confidence: 99%

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

et al. 2009

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“…Synthetic PIM-PIM 1 containing a C16 and a C18 chain in the glycerolipid unit was prepared following largely published procedures (30,32,35,36) with some modifications (for details, see the supplemental information). The reference compound phosphatidylinositol (PI) was prepared by an analogous method.…”

Section: Methodsmentioning

confidence: 99%

Mycobacterial Phosphatidylinositol Mannosides Negatively Regulate Host Toll-like Receptor 4, MyD88-dependent Proinflammatory Cytokines, and TRIF-dependent Co-stimulatory Molecule Expression

Doz

Rose

Court

et al. 2009

Journal of Biological Chemistry

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Mycobacterium tuberculosis modulates host immune responses through proteins and complex glycolipids. Here, we report that the glycosylphosphatidylinositol anchor phosphatidyl-myo-inositol hexamannosides PIM 6 or PIM 2 exert potent anti-inflammatory activities. PIM strongly inhibited the Tolllike receptor (TLR4) and myeloid differentiation protein 88 (MyD88)-mediated release of NO, cytokines, and chemokines, including tumor necrosis factor (TNF), interleukin 12 (IL-12) p40, IL-6, keratinocyte-derived chemokine, and also IL-10 by lipopolysaccharide (LPS)-activated macrophages. This effect was independent of the presence of TLR2. PIM also reduced the LPS-induced MyD88-independent, TIR domain-containing adaptor protein inducing interferon ␤ (TRIF)-mediated expression of co-stimulatory receptors. PIM inhibited LPS/TLR4-induced NFB translocation. Synthetic PIM 1 and a PIM 2 mimetic recapitulated these in vitro activities and inhibited endotoxininduced airway inflammation, TNF and keratinocyte-derived chemokine secretion, and neutrophil recruitment in vivo. Mannosyl, two acyl chains, and phosphatidyl residues are essential for PIM anti-inflammatory activity, whereas the inosityl moiety is dispensable. Therefore, PIM exert potent antiinflammatory effects both in vitro and in vivo that may contribute to the strategy developed by mycobacteria for repressing the host innate immunity, and synthetic PIM analogs represent powerful antiinflammatory leads.

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“…The excellent regioselectivity is perhaps induced by the steric hindrance of both O-2-and O-6-mannosyl rings preventing the nucleophilic attack of O-1 to benzA C H T U N G T R E N N U N G aldehyde. Coupling of compound 29 with the H-phosphonA C H T U N G T R E N N U N G ate 3 [8] by using a combination of pivaloyl chloride, iodine, and pyridine furnished the product 30 [18] (82 %), which was subjected to hydrogenolysis to give the target molecule 1 [18] in 52 % yield. The 1 H and 13 C NMR spectra of compounds 29, [17] 30, [18] and 1 [18] are identical to the literature reports (see Supporting Information).…”

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Total Synthesis of Phosphatidylinositol Dimannoside: A Cell‐Envelope Component of Mycobacterium tuberculosis

Patil

Hung

2009

Chemistry A European J

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Phosphatidylinositol mannosides: Synthesis and suppression of allergic airway disease

Cited by 37 publications

References 32 publications

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

Mycobacterial Phosphatidylinositol Mannosides Negatively Regulate Host Toll-like Receptor 4, MyD88-dependent Proinflammatory Cytokines, and TRIF-dependent Co-stimulatory Molecule Expression

Total Synthesis of Phosphatidylinositol Dimannoside: A Cell‐Envelope Component of Mycobacterium tuberculosis

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