Lipoarabinomannan of Mycobacterium tuberculosisPromotes Protein Tyrosine Dephosphorylation and Inhibition of Mitogen-activated Protein Kinase in Human Mononuclear Phagocytes

Knutson, Keith L.; Hmama, Zakaria; Herrera-Velit, Patricia; Rochford, Rosemary; Reiner, Neil E.

doi:10.1074/jbc.273.1.645

Cited by 147 publications

(123 citation statements)

References 53 publications

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“…At present, it is unclear how ManLAMs can interfere with this signaling pathway through MR ligation. ManLAMs were found to alter signaling pathway activation of human mononuclear phagocytes by promoting the tyrosine phosphatase 1 (SHP-1), a tyrosine phosphatase known to be important for attenuating activation signals (19). It is conceivable that ManLAMs exert their inhibitory effects by inducing the dephosphorylation of multiple proteins, including mitogen-activated protein kinase, involved in the IL-12 signaling pathway.…”

Section: Figurementioning

confidence: 99%

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Mannosylated Lipoarabinomannans Inhibit IL-12 Production by Human Dendritic Cells: Evidence for a Negative Signal Delivered Through the Mannose Receptor

Nigou

Zelle‐Rieser

Gilleron

et al. 2001

The Journal of Immunology

370

336

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IL-12 is a key cytokine in directing the development of type 1 Th cells, which are critical to eradicate intracellular pathogens such as Mycobacterium tuberculosis. Here, we report that mannose-capped lipoarabinomannans (ManLAMs) from Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis inhibited, in a dose-dependant manner, the LPS-induced IL-12 production by human dendritic cells. The inhibitory activity was abolished by the loss of the mannose caps or the GPI acyl residues. Mannan, which is a ligand for the mannose receptor (MR) as well as an mAb specific for the MR, also inhibited the LPS-induced IL-12 production by dendritic cells. Our results indicate that ManLAMs may act as virulence factors that contribute to the persistence of M. bovis bacillus Calmette-Guérin and M. tuberculosis within phagocytic cells by suppressing IL-12 responses. Our data also suggest that engagement of the MR by ManLAMs delivers a negative signal that interferes with the LPS-induced positive signals delivered by the Toll-like receptors.

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Section: Figurementioning

confidence: 99%

“…16 -18). Conversely, M. tuberculosis ManLAMs were shown to attenuate TNF-␣ and IL-12 expression in human mononuclear phagocytes (19). Additionally, M. bovis BCG and M. tuberculosis ManLAMs were found to bind murine and human macrophages via the mannose receptor (MR; Ref.…”

mentioning

confidence: 99%

Mannosylated Lipoarabinomannans Inhibit IL-12 Production by Human Dendritic Cells: Evidence for a Negative Signal Delivered Through the Mannose Receptor

Nigou

Zelle‐Rieser

Gilleron

et al. 2001

The Journal of Immunology

370

336

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“…The early response genes c-fos, KC, and JE are induced by ara-LAM but not by man-LAM (15). The ability of man-LAM to impair responsiveness to interferon-␥ and to attenuate tumor necrosis factor-␣ and interleukin-12 mRNA production through effects on the protein phosphatase SHP-1 has been suggested to be a major mechanism by which man-LAM promotes intracellular survival (16).…”

mentioning

confidence: 99%

Lipoarabinomannan from Mycobacterium tuberculosis Promotes Macrophage Survival by Phosphorylating Bad through a Phosphatidylinositol 3-Kinase/Akt Pathway

Maiti

Bhattacharyya

Basu

2001

Journal of Biological Chemistry

135

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“…These subtle differences in the capping motifs are thought to explain the different immunomodulatory functions of ManLAM and PILAM. ManLAMs have the ability to inhibit the production of pro-inflammatory cytokines, such as IL-12 and TNF-a (Knutson et al, 1998;Nigou et al, 2001) and conversely PILAM stimulates the production of these pro-inflammatory cytokines (Adams et al, 1993;Gilleron et al, 1997). These facts not only corroborate the findings that slow-growing mycobacteria have the ability to exist and multiply within phagocytic cells and fast-growing mycobacteria do not, but illustrate the importance of ManLAM as a key virulence factor enabling the persistence of slow-growing mycobacteria within phagocytic cells (Nigou et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Structural and functional features of Rhodococcus ruber lipoarabinomannan

et al. 2003

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The genus Rhodococcus is part of the phylogenetic group nocardioform actinomycetes, which also includes the genus Mycobacterium. Members of this phylogenetic group have a characteristic cell envelope structure, which is dominated by various complex lipids. Among these, lipoglycans are of particular interest since mycobacterial lipoarabinomannans are important immunomodulatory molecules that are likely to be involved in the subsequent fate of mycobacterial bacilli once inside phagocytic cells. Rhodococcus ruber is a species closely related to an established opportunistic human pathogen, Rhodococcus equi. This paper reports the isolation and characterization of R. ruber lipoarabinomannan, designated as RruLAM. SDS-PAGE and gas chromatography analyses revealed that RruLAM was of an intermediate size between Mycobacterium tuberculosis lipoarabinomannan and lipomannan. Using a combination of chemical degradation and 1 H, 13 C-NMR experiments, the carbohydrate structure of RruLAM was unambiguously shown to be composed of a linear (a1R6)-Manp backbone substituted at some O-2 positions by a single t-a-Araf sugar unit. Integration of the anomeric proton signals provided an indication of the degree of branching as approximately 45 %. The RruLAM structure is much simpler than that established for M. tuberculosis lipoarabinomannan but is also different from that determined for the closely related species and opportunistic human pathogen, R. equi. RruLAM was unable to induce the production of TNF-a by either human or murine macrophage cell lines, suggesting that more sophisticated structures, such as phosphoinositol capping motifs, are required for such activity.

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Lipoarabinomannan of Mycobacterium tuberculosisPromotes Protein Tyrosine Dephosphorylation and Inhibition of Mitogen-activated Protein Kinase in Human Mononuclear Phagocytes

Abstract: Lipoarabinomannan (LAM) is a putative virulence factor of

Cited by 147 publications

References 53 publications

Mannosylated Lipoarabinomannans Inhibit IL-12 Production by Human Dendritic Cells: Evidence for a Negative Signal Delivered Through the Mannose Receptor

Mannosylated Lipoarabinomannans Inhibit IL-12 Production by Human Dendritic Cells: Evidence for a Negative Signal Delivered Through the Mannose Receptor

Lipoarabinomannan from Mycobacterium tuberculosis Promotes Macrophage Survival by Phosphorylating Bad through a Phosphatidylinositol 3-Kinase/Akt Pathway

Structural and functional features of Rhodococcus ruber lipoarabinomannan

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