<i>Pneumocystis</i>Cell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism

Carmona, Eva M.; Vassallo, Robert; Vuk-Pavlović, Zvezdana; Standing, Joseph E.; Kottom, Theodore J.; Limper, Andrew H.

doi:10.4049/jimmunol.177.1.459

Cited by 66 publications

(73 citation statements)

References 37 publications

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“…We previously showed that human DCs stimulated with PCBG are potent inducers of some features of the Th1 phenotype, in the absence of IL-12 (31). The lack of the p35 subunit, rather than the abundant p40 subunit, was determined to be the main reason for deficiency of total IL-12.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that human DCs stimulated with PCBG are potent inducers of a Th1 phenotype in the absence of IL-12 (31). Over the last several years, Th17 cells have been described as important components necessary for the clearance of fungal infections, including Pneumocystis pneumonia (19)(20)(21).…”

Section: Pcbg Induce Activation Of the Human Il-23/il-17 Axismentioning

confidence: 99%

“…The main functions of b-glucans were originally believed to be related primarily to fungal cell-wall structural integrity. However, we know now that these cell-wall components are additionally able to trigger inflammatory responses in various immune and nonimmune cell types (31)(32)(33)(34)(35)(36)(37). In particular, we showed that DCs stimulated with particulate, nonsoluble PCBG are important inducers of Th1 responses, and that these responses are mainly driven by IL-1b secretion (31).…”

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confidence: 99%

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Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

Carmona

Kottom

Hebrink

et al. 2012

Am J Respir Cell Mol Biol

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Pneumocystis species are opportunistic fungal organisms that cause severe pneumonia in immune-compromised hosts, with resultant high morbidity and mortality. Recent work indicates that IL-17 responses are important components of host defense against fungal pathogens. In the present study, we demonstrate that cellsurface b-glucan components of Pneumocystis (PCBG) stimulate human dendritic cells (DCs) to secrete IL-23 and IL-6. These cytokines are well established to stimulate a T helper-17 (Th17) phenotype. Accordingly, we further observe that PCBG-stimulated human DCs interact with lymphocytes to drive the secretion of IL-17 and IL-22, both Th17-produced cytokines. The activation of DCs was shown to involve the dectin-1 receptor with a downstream activation of the Syk kinase and subsequent translocation of both the canonical and noncanonical components of the NF-kB transcription factor family. Finally, we demonstrate that glycosphingolipid-rich microdomains of the plasma membrane participate in the activation of DCs by PCBG through the accumulation of lactosylceramide at the cell surface during stimulation with PCBG. These data strongly support the idea that the b-glucan surface components of Pneumocystis drive the activation of the IL-23/IL-17 axis during this infection, through a glycosphingolipid-initiated mechanism.Keywords: Pneumocystis; b-glucan; dendritic cells; Pneumocystis infection remains an all too common cause of pneumonia in immune-compromised hosts. Before the early 1990s, this infection was largely related to cases of childhood leukemia and infants with severe malnourishment. However, with the onset of the HIV pandemic, Pneumocystis pneumonia (PcP) has emerged as one of most serious causes of pneumonia among this patient population (1-3). In more recent years, an increasing number of PcP cases have been attributed to immunosuppressed individuals with malignancy, or as a result of immunosuppressive agents administered for organ transplantation or autoimmune diseases (4-10).Earlier studies established the central importance of T cells in the host defense against Pneumocystis infection, where CD4 cell counts of less than 200 cells/mm 3 were shown to place individuals at increased risk for this infection (11). More recently, CD4-independent mechanisms were also demonstrated to be important in clearing this infection (12). This is also supported by the fact that patients receiving B cell-suppressive therapy, and animal models of B-cell deficiency, also reveal a higher risk for developing PcP (13,14). Thus, inadequate immune response across multiple components of host defense can render an individual susceptible to this infection.In addition, exaggerated innate inflammatory responses in patients with PcP appear to be associated with a higher risk of developing respiratory failure, as indicated by early work from our laboratory showing that the degree of respiratory failure in immunosuppressed patients with PcP correlated best with the degree of inflammation, and not with the organism burden itself (15...

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Section: Discussionmentioning

confidence: 99%

Section: Pcbg Induce Activation Of the Human Il-23/il-17 Axismentioning

confidence: 99%

mentioning

confidence: 99%

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Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

Carmona

Kottom

Hebrink

et al. 2012

Am J Respir Cell Mol Biol

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“…The Sophy β-glucan-induced sFas production by cultured PBMCs or U937 cells observed in this study suggests that Sophy β-glucan might prevent apoptosis by suppressing the Fas/FasL apoptosis induction system, and that Sophy β-glucan might be used to examine the role of apoptosis in the maintenance of homeostasis. For example, it was recently reported that the β-glucans contained within the cell wall of Pneumocystis induced costimulatory molecular expression in dendritic cells (DCs) and inflammatory activation mediated by the Fas/FasL apoptosis induction system (6). If Sophy β-glucan-induced sFas production by PBMCs can prevent the onset of apoptosis regulated by the Fas/FasL system, then Sophy β-glucan may have the potential ability to downregulate inflammatory responses.…”

Section: Immunological Actions Of Sophy β-Glucanmentioning

confidence: 99%

Immunological Actions of Sophy β‐Glucan (β‐1,3‐1,6 Glucan), Currently Available Commercially as a Health Food Supplement

Ikewaki

Fujii²,

Onaka³

et al. 2007

Microbiology and Immunology

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-4). In these blocking experiments using the mAbs, the main differences in the results between PBMCs and U937 cells were that the mAbs against TLR-2 and TLR-4 did not block the Sophy ␤-glucan-induced production of IL-8 in the U937 cells. Furthermore, a mAb to the ␤-glucan receptor, Dectin-1, significantly (P<0.05) blocked the Sophy ␤-glucaninduced DNA synthesis in the PBMCs, and Sophy ␤-glucan-induced production of IL-8 in the U937 cells. The Sophy ␤-glucan-induced production of IL-8 in the U937 cells was significantly (P<0.01) blocked by the conventional protein kinase C (PKC) inhibitor Go6976, the novel PKC inhibitor Rottlerin, the protein kinase A (PKA) inhibitor H-89, and the protein tyrosine kinase (PTK) inhibitor herbimycin A. Among these, the blocking effect of the novel PKC (PKC delta isoenzyme) inhibitor Rottlerin was the most pronounced. Studies employing reverse transcriptase-polymerase chain reaction (RT-PCR) showed that Sophy ␤-glucan stimulated the expression of IL-8 mRNA in the U937 cells, and that this induction was inhibited by Rottlerin. Sophy ␤-glucan also blocked the stimulator cell induction of DNA synthesis and IFN-␥ production in the responder cells in a one-way mixed lymphocyte reaction (MLR) using allogenic PBMCs. Interestingly, immunoglobulin G (IgG), but not IgM to Sophy ␤-glucan was detected in the sera derived from normal adult donors and from the umbilical cord blood of neonates. Taken together, these findings strongly suggest that the Sophy ␤-glucan may have unique immune regulatory or enhancing properties that could be exploited by the health food, medical and pharmaceutical industries.

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“…It is considered that by enabling DC maturation and activation, β-glucan activates cytokine response, and so it is considered to effect the regulation of immune response [19]. Kikuchi et al have also reported that Candida β-glucan may augment DC maturation [15].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Effects of Candida albicans and Aspergillus fumigatus on Dendritic Cells and the Role of Beta Glucan in this Effect

Fidan¹,

Kalkancı²,

Yeşilyurt³

et al. 2014

Adv Clin Exp Med

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Background. Dendritic cells (DCs) are able to initiate and regulate the immune response to fungal infections. β-glucan stimulates the immune system, modulating cellular and humoral immunity. It has a beneficial effect in fighting fungal infections. Objectives. We investigated the in vitro effect of C.albicans and A.fumigatus infection on human DCs. The cytokine levels were determined by ELISA. Material and Methods. Human PBMCs isolation was performed by Ficoll-hypaque density gradient centrifugation method. DCs maturation was analysed by using flow cytometry. The cytokine levels were determined by ELISA. Results. DCs stimulated by C. albicans and A. fumigatus induced DC maturation by increasing CD80 and CD86 co-stimulatory molecules. DCs stimulated by fungi produced IL-8 and IL-12p70. Whereas IL-10 production from the stimulated DCs did not differ from uninfected DCs. Also, the addition of β-glucan to the DCs stimulated by fungi promoted the activation and maturation of DCs. Conclusions. Our results suggest that DCs are capable of initiating an innate and adaptive immune response against fungal infections. In addition, β-glucan can be used as a novel stimulator to DC-based vaccination against fungal infections (Adv Clin Exp Med 2014, 23, 1, 17-24).

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

Cited by 66 publications

References 37 publications

Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

Immunological Actions of Sophy β‐Glucan (β‐1,3‐1,6 Glucan), Currently Available Commercially as a Health Food Supplement

In Vitro Effects of Candida albicans and Aspergillus fumigatus on Dendritic Cells and the Role of Beta Glucan in this Effect

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