Inhibition of FcεRI-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 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.

RETRACTED: The cytokine interleukin-33 mediates anaphylactic shock

“…In Vitro Assays. Human mast cells were derived from CD34 ϩ hematopoietic progenitor cells isolated from umbilical cord blood and cultured as previously described (26,34). Murine mast cells were isolated from the peritoneal cavity and cultured as previously described (35).…”

“…Similar results were observed for murine mast cells (data not shown). We have previously shown that at least two different pathways are used by antigen and cytokine receptors to trigger cytosolic calcium signals: the classical pathway that activates phospholipase C to generate IP 3 (22,23), and a novel pathway dependent on the activation of phospholipase D (PLD) and sphingosine kinase (SphK) (24)(25)(26). IL-33 triggered the activation and translocation of PLD1 (Fig.…”

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

“…Among others, a phosphatidylserine with specific chain length expressed by S. mansoni eggs engages TLR2 expressed on dendritic cells, which in turn induces IL-10-producing regulatory T cells (53). A secreted glycoprotein of the filarial nematode A. viteae inhibited Fc RImediated mast cell responses by forming a complex with TLR4, which resulted in the sequestration of protein kinase C-␣, a molecule important for mast cell activation (54,55). We provide evidence that cystatin protects from inflammation in a systemic fashion, as reflected by its effects on remarkably different compartments, such as the lung and the gut.…”

Cutting Edge: Mast Cells Express IL-17A in Rheumatoid Arthritis Synovium

“…Human mast cells were derived from CD34 + hematopoietic progenitor cells isolated from umbilical cord blood and cultured as described previously (13,14). Mast cells were stimulated with TNF-a (10 ng/ml), IgG complexes (100 ng/ml), C5a (5 ng/ml), or LPS (10 ng/ml) for 24 h, and supernatant was tested for IL-1b, IL-5, IL-6, and IL-17A by ELISA (ELISA kits from eBioscience, Hatfield, U.K.).…”