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

Harnett, M. M. , Harnett, W., McSharry, C. P., Melendez, A. J., Pushparaj, P. N., Tay, H. K. and Wong, W. S. F. (2007) Inhibition of FcεRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nature Medicine, 13(11), pp. 1375-1381. (doi:10.1038/nm1654)

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Publisher's URL: http://dx.doi.org/10.1038/nm1654

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Tay, Dr Hwee Kee
Authors: Harnett, M. M., Harnett, W., McSharry, C. P., Melendez, A. J., Pushparaj, P. N., Tay, H. K., and Wong, W. S. F.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nature Medicine
Publisher:Nature Publishing Group
ISSN:1078-8956
ISSN (Online):1546-170X
Published Online:21 October 2007
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
462311Therapeutic potential of Sphingosine Kinase blockage in allergic anaphylaxis.Alirio Melendez RomeroMedical Research Council (MRC)G0700794Institute of Infection Immunity and Inflammation