The role of individual protein kinase C isoforms in mouse mast cell function and their targeting by the immunomodulatory parasitic worm product, ES-62

Bell, K. S., Al-Riyami, L., Lumb, F. E., Britton, G. J., Poole, A. W., Williams, C. M., Braun, U., Leitges, M., Harnett, M. and Harnett, W. (2015) The role of individual protein kinase C isoforms in mouse mast cell function and their targeting by the immunomodulatory parasitic worm product, ES-62. Immunology Letters, 168(1), pp. 31-40. (doi:10.1016/j.imlet.2015.09.001) (PMID:26343793) (PMCID:PMC464348)

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Abstract

ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, has been shown to modulate the immune system through subversion of signal transduction pathways operating in various immune system cells. With respect to human bone marrow-derived mast cells (BMMCs), ES-62 was previously shown to inhibit FcϵRI-mediated mast cell functional responses such as degranulation and pro-inflammatory cytokine release through a mechanism involving the degradation of PKC-α. At the same time, it was noted that the worm product was able to degrade certain other PKC isoforms but the significance of this was uncertain. In this study, we have employed PKC isoform KO mice to investigate the role of PKC-α, -β -ϵ, and -θ in mouse BMMCs in order to establish their involvement in mast cell-mediated responses and also, if their absence impacts on ES-62’s activity. The data obtained support that in response to antigen cross-linking of IgE bound to FcϵRI, pro-inflammatory cytokine release is controlled in part by a partnership between one conventional and one novel isoform with PKC-α and -θ acting as positive regulators of IL-6 and TNF-α production, while PKC-β and ϵ act as negative regulators of such cytokines. Furthermore, ES-62 appears to target certain other PKC isoforms in addition to PKC-α to inhibit cytokine release and this may enable it to more efficiently inhibit mast cell responses.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret
Authors: Bell, K. S., Al-Riyami, L., Lumb, F. E., Britton, G. J., Poole, A. W., Williams, C. M., Braun, U., Leitges, M., Harnett, M., and Harnett, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Immunology Letters
ISSN:01652478
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Immunology Letters 168(1):31-40
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
495342ES-62, TLR4, the Mast Cell and development of novel drugs for mast cell-mediated inflammationMargaret HarnettWellcome Trust (WELLCOME)086852/Z/08/ZIII -IMMUNOLOGY