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

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 Fc epsilon RI-mediated mast cell functional responses such as degranulation and pro-inflammatory cytokine release through a mechanism involving the degradation of PKC-alpha. 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-alpha, -beta -epsilon, and -theta 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 REM, pro-inflammatory cytokine release is controlled in part by a partnership between one conventional and one novel isoform with PKC-alpha and -theta acting as positive regulators of IL-6 and TNF-alpha production, while PKC-beta and epsilon act as negative regulators of such cytokines. Furthermore, ES-62 appears to target certain other PKC isoforms in addition to PKC-alpha to inhibit cytokine release and this may enable it to more efficiently inhibit mast cell responses. (C) 2015 The Authors. Published by Elsevier B.V.