Letter abstract
Nature Medicine 13, 1375 - 1381 (2007)
Published online: 21 October 2007 | doi:10.1038/nm1654
Inhibition of Fc
RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes
Alirio J Melendez1, Margaret M Harnett2, Peter N Pushparaj1, WS Fred Wong3, Hwee Kee Tay1, Charles P McSharry2 & William Harnett4
Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fc
receptor (FcRI) 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 FcRI-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-
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-
(PKC-). This causes caveolae/lipid raft–mediated, proteasome-independent degradation of PKC-, a molecule important for the coupling of FcRI 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.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive MD9, Singapore 117597.
- Division of Immunology, Infection and Inflammation, Glasgow University, 120 University Place, Glasgow G12 8TA, UK.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive MD2, Singapore 117597.
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, 27 Taylor Street, Glasgow G4 0NR, UK.
Correspondence to: William Harnett4 e-mail: w.harnett@strath.ac.uk
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