Pneumocystis carinii Cell Wall β-Glucan Induces Release of Macrophage Inflammatory Protein-2 from Alveolar Epithelial Cells via a Lactosylceramide-mediated Mechanism

Hahn, Peter Y.; Evans, Scott E.; Kottom, Theodore J.; Standing, Joseph E.; Pagano, Richard E.; Limper, Andrew H.

doi:10.1074/jbc.m209715200

Cited by 139 publications

(164 citation statements)

References 43 publications

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“…Other investigations have demonstrated that dectin-1 may act synergistically with TLR2 to mediate cytokine generation by DCs and macrophages in response to zymosan, a glucan-rich cell wall fraction of yeast (35). However, other investigations indicate that under other conditions, cells of the lower respiratory tract can respond to fungal ␤-glucans in the absence of dectin-1 (12,32). In this light, other receptors including lactosylceramide can also independently mediate host inflammatory signaling to Pneumocystis and other fungal cell wall ␤-glucans (12,32,36,37).…”

Section: Discussionmentioning

confidence: 88%

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PneumocystisCell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism

Carmona

Vassallo

Vuk-Pavlović

et al. 2006

The Journal of Immunology

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Respiratory failure during Pneumocystis pneumonia is mainly a consequence of exaggerated inflammatory responses to the organism. Dendritic cells (DCs) are the most potent APCs in the lung and are key to the regulation of innate and adaptive immune responses. However, their participation in the inflammatory response directed against Pneumocystis infection has not been fully elucidated. Therefore, we studied the role of Pneumocystis carinii, as well as Saccharomyces cerevisiae, cell wall-derived β-glucans, in DC costimulatory molecule expression. We further studied the impact of β-glucans on subsequent T cell activation. Because cytokine secretion by DCs has recently been shown to be regulated by Fas ligand (FasL), its role in β-glucan activation of DCs was also investigated. β-Glucan-induced DC activation occurred in part through dectin-1 receptors. We demonstrated that DC activation by β-glucans elicits T cell activation and polarization into a Th1 patterned response, but with the conspicuous absence of IL-12. These observations differed from LPS-driven T cell polarization, suggesting that β-glucans and LPS signal DC activation through different mechanisms. We additionally determined that IL-1β and TNF-α secretion by β-glucan-stimulated DCs was partially regulated by Fas-FasL. This suggests that dysregulation of FasL could further enhance exuberant and prolonged cytokine production by DCs following DC-T cell interactions, further promoting lung inflammation typical of Pneumocystis pneumonia.

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Section: Discussionmentioning

confidence: 88%

“…A glucan-rich cell wall fraction from Pneumocystis was prepared, as previously described (5,12). Pneumocystis pneumonia was induced in dexamethasone-treated immunosuppressed Long-Evans rats (Harlan) (11).…”

Section: Generation Of a Pneumocystis Glucan-rich Cell Wall Isolatementioning

confidence: 99%

PneumocystisCell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism

Carmona

Vassallo

Vuk-Pavlović

et al. 2006

The Journal of Immunology

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“…P. carinii organisms were isolated from lungs of heavily infected animals by homogenization and filtration through 10-m filters. The organisms were autoclaved (120°C, 20 min) and disrupted by ultrasonication (200 W for 3 min, six times), and the glucans were isolated by NaOH digestion and lipid extraction as previously detailed (6,7). The final product contained predominantly carbohydrate (95.7%) and released 82% of its content as D-glucose following hydrolysis (6).…”

Section: Methodsmentioning

confidence: 99%

“…A glucan-rich cell wall fraction from P. carinii was prepared as recently described (6,7). P. carinii pneumonia was induced in dexamethasone-treated immunosuppressed Harlan Sprague-Dawley rats (Harlan, Inc., Indianapolis, IN) (8).…”

Section: Methodsmentioning

confidence: 99%

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Pneumocystis carinii Cell Wall β-Glucans Initiate Macrophage Inflammatory Responses through NF-κB Activation

Lebron¹,

Vassallo²,

Puri³

et al. 2003

Journal of Biological Chemistry

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110

101

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␤-Glucans are major structural components of fungi. We have recently reported that the pathogenic fungus Pneumocystis carinii assembles a ␤-glucan-rich cell wall that potently activates alveolar macrophages to release pro-inflammatory cytokines and chemokines. Purified P. carinii ␤-glucans predictably induce both cytokine generation and associated neutrophilic lung inflammation. Herein, we demonstrate that P. carinii ␤-glucaninduced macrophage stimulation results from activation of NF-B. Although analogous to macrophage activation induced by bacterial lipopolysaccharide (LPS), P. carinii ␤-glucan-induced macrophage NF-B activation exhibits distinctly different kinetics, with slower induction and longer duration compared with LPS stimulation. Macrophage activation in response to P. carinii ␤-glucan was also substantially inhibited with the NF-B antagonist pyrrolidine dithiocarbamate. In addition to different kinetics of NF-B activation, P. carinii ␤-glucan and LPS also utilize different receptor systems to induce macrophage activation. Macrophages from Toll-like receptor 4-deficient and wild type mice produced equivalent amounts of tumor necrosis factor ␣ when stimulated with P. carinii ␤-glucan. However, Toll-like receptor 4-deficient macrophages were refractory to stimulation with LPS. In contrast, MyD88-deficient macrophages exhibited a significant (though partial) blunted response to P. carinii ␤-glucan. These data demonstrate that P. carinii ␤-glucan acts as potent inducer of macrophage activation through NF-B utilizing cellular receptors and signaling pathways distinct from LPS.

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The regulatory roles of glycosphingolipid‐enriched lipid rafts in immune systems

et al. 2018

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Lipid rafts formed by glycosphingolipids (GSLs) on cellular membranes play important roles in innate and adaptive immunity. Lactosylceramide (LacCer) forms lipid rafts on plasma and granular membranes of human neutrophils. These LacCer‐enriched lipid rafts bind directly to pathogenic components, such as pathogenic fungi‐derived β‐glucan and Mycobacteria‐derived lipoarabinomannan via carbohydrate‐carbohydrate interactions, and mediate innate immune responses to these pathogens. In contrast, a‐series and o‐series gangliosides form distinct rafts on CD4+ and CD8+ T cell subsets, respectively, contributing to the respective functions of these cells and stimulating adaptive immune responses through T cell receptors. These findings suggest that gangliosides play indispensable roles in T cell selection and activation. This Review introduces the involvement of GSL‐enriched lipid rafts in innate and adaptive immunity.

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Pneumocystis carinii Cell Wall β-Glucan Induces Release of Macrophage Inflammatory Protein-2 from Alveolar Epithelial Cells via a Lactosylceramide-mediated Mechanism

Cited by 139 publications

References 43 publications

PneumocystisCell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism

PneumocystisCell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism

Pneumocystis carinii Cell Wall β-Glucans Initiate Macrophage Inflammatory Responses through NF-κB Activation

The regulatory roles of glycosphingolipid‐enriched lipid rafts in immune systems

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