Inhibition of FceRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes

A.J. Melendez, M.M. Harnett, P.N. Pushparaj, W.S.F. Wong, H.K. Tay, C.P. McSharry, W. Harnett

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world1. However, this increase has not been mirrored in developing countries2, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms3. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes4. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.
LanguageEnglish
Pages1375-1381
Number of pages6
JournalNature Medicine
Volume13
Issue number11
DOIs
Publication statusPublished - 2007

Fingerprint

Allergies
Mast Cells
Immunoglobulin E
Protein Kinase C-alpha
Phospholipase D
Hypersensitivity
Chemical activation
Signal transduction
Toll-Like Receptor 4
Molecules
Proteasome Endopeptidase Complex
Endotoxins
Caveolae
Somatostatin-Secreting Cells
Skin
Calcium
Lipids
Degradation
Signal Transduction
Antibodies

Keywords

  • pharmacology
  • nematodes
  • cells
  • allergies
  • biomedicine

Cite this

Melendez, A. J., Harnett, M. M., Pushparaj, P. N., Wong, W. S. F., Tay, H. K., McSharry, C. P., & Harnett, W. (2007). Inhibition of FceRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nature Medicine, 13(11), 1375-1381. https://doi.org/10.1038/nm1654
Melendez, A.J. ; Harnett, M.M. ; Pushparaj, P.N. ; Wong, W.S.F. ; Tay, H.K. ; McSharry, C.P. ; Harnett, W. / Inhibition of FceRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. In: Nature Medicine. 2007 ; Vol. 13, No. 11. pp. 1375-1381.
@article{fecb0fc35be74d3eb999dc53b7b0ca4c,
title = "Inhibition of FceRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes",
abstract = "Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world1. However, this increase has not been mirrored in developing countries2, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms3. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes4. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.",
keywords = "pharmacology, nematodes, cells, allergies, biomedicine",
author = "A.J. Melendez and M.M. Harnett and P.N. Pushparaj and W.S.F. Wong and H.K. Tay and C.P. McSharry and W. Harnett",
year = "2007",
doi = "10.1038/nm1654",
language = "English",
volume = "13",
pages = "1375--1381",
journal = "Nature Medicine",
issn = "1078-8956",
number = "11",

}

Melendez, AJ, Harnett, MM, Pushparaj, PN, Wong, WSF, Tay, HK, McSharry, CP & Harnett, W 2007, 'Inhibition of FceRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes' Nature Medicine, vol. 13, no. 11, pp. 1375-1381. https://doi.org/10.1038/nm1654

Inhibition of FceRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. / Melendez, A.J.; Harnett, M.M.; Pushparaj, P.N.; Wong, W.S.F.; Tay, H.K.; McSharry, C.P.; Harnett, W.

In: Nature Medicine, Vol. 13, No. 11, 2007, p. 1375-1381.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of FceRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes

AU - Melendez, A.J.

AU - Harnett, M.M.

AU - Pushparaj, P.N.

AU - Wong, W.S.F.

AU - Tay, H.K.

AU - McSharry, C.P.

AU - Harnett, W.

PY - 2007

Y1 - 2007

N2 - Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world1. However, this increase has not been mirrored in developing countries2, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms3. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes4. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.

AB - Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world1. However, this increase has not been mirrored in developing countries2, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms3. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes4. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.

KW - pharmacology

KW - nematodes

KW - cells

KW - allergies

KW - biomedicine

UR - http://www.nus.edu.sg/ngs/supervisor_publications/alirio_jose_melendez/Nat.Med.Article.11.07.pdf

UR - http://dx.doi.org/10.1038/nm1654

U2 - 10.1038/nm1654

DO - 10.1038/nm1654

M3 - Article

VL - 13

SP - 1375

EP - 1381

JO - Nature Medicine

T2 - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 11

ER -

Melendez AJ, Harnett MM, Pushparaj PN, Wong WSF, Tay HK, McSharry CP et al. Inhibition of FceRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nature Medicine. 2007;13(11):1375-1381. https://doi.org/10.1038/nm1654