Inhibition of Fc|[epsi]|RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes

doi:doi:10.1038/nm1654

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fc epsilon receptor (Fc epsilon RI) 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 Fc epsilon RI-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- kappa B 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 Fc epsilon RI 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.

Access

Letter

Article Links

Article Tools

Search Pubmed for

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

Abstract

MORE ARTICLES LIKE THIS

NEWS AND VIEWS

RESEARCH