Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes.
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 world. However, this increase has not been mirrored in developing countries, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes. 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.
Melendez
Alirio J
AJ
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive MD9, Singapore 117597.
Harnett
Margaret M
MM
Pushparaj
Peter N
PN
Wong
W S Fred
WS
Tay
Hwee Kee
HK
McSharry
Charles P
CP
Harnett
William
W
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D005370:Filarioidea / Q000276:immunology*; D015801:Helminth Proteins / Q000502:physiology*; D006801:Humans; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology
C435884:ES-62 protein, Acanthocheilonema viteae; D015801:Helminth Proteins; D017455:Receptors, IgE; D051571:Protein Kinase C-alpha; D002118:Calcium