The role of individual protein kinase C isoforms in mouse mast cell function and their targeting by the immunomodulatory parasitic worm product, ES-62.
The role of individual protein kinase C isoforms in mouse mast cell function and their targeting by the immunomodulatory parasitic worm product, ES-62.
复制标题
单个蛋白激酶C同工型在小鼠肥大细胞功能中的作用以及免疫调节性寄生虫产物ES-62的靶向。
DOI：
10.1016/j.imlet.2015.09.001
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发表时间：
2015-11
影响因子：
4.4
通讯作者：
Harnett W
中科院分区：
文献类型：
--
作者：
Bell KS;Al-Riyami L;Lumb FE;Britton GJ;Poole AW;Williams CM;Braun U;Leitges M;Harnett MM;Harnett W
蛋白激酶C基因敲除小鼠已被用于探索肥大细胞（MC）功能中的作用。单个PKC亚型可正向或负向调节MC细胞因子反应。MC中的某些PKC亚型被寄生虫产物ES-62靶向。ES-62是一种由丝状线虫Acanthocheilonema viteae分泌的糖蛋白，已显示通过破坏在各种免疫系统细胞中操作的信号转导途径来调节免疫系统。对于人骨髓源性肥大细胞（BMMC），先前已证明ES-62可通过涉及PKC-α降解的机制抑制Fcε RI介导的肥大细胞功能反应，如脱粒和促炎细胞因子释放。同时，注意到蠕虫产物能够降解某些其他PKC亚型，但其意义尚不确定。在这项研究中，我们使用PKC亚型KO小鼠来研究PKC-α，-β -κ B和-θ在小鼠BMMC中的作用，以确定它们是否参与肥大细胞介导的反应，以及它们的缺失是否影响ES-62的活性。获得的数据支持，在应答IgE与Fc β RI结合的抗原交联时，促炎细胞因子释放部分受一种常规亚型和一种新型亚型之间的伙伴关系控制，其中PKC-α和-θ作为IL-6和TNF-α产生的正调节剂，而PKC-β和PKC β作为此类细胞因子的负调节剂。此外，ES-62似乎靶向除PKC-α以外的某些其他PKC亚型以抑制细胞因子释放，这可能使其能够更有效地抑制肥大细胞反应。
Knock out mice have been used to explore the role of PKCs in mast cell (MC) function. Individual PKC isoforms may positively or negatively regulate MC cytokine responses. Certain PKC isoforms in MCs are targeted by the 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 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.