PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness.,Journal of Allergy and Clinical Immunology

当前位置： X-MOL 学术 › J. Allergy Clin. Immunol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness.
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-05-11 , DOI: 10.1016/j.jaci.2020.03.046
Shruti Rastogi ₁ , Diana Maria Willmes ₁ , Maria Nassiri ₁ , Magda Babina ₁ , Margitta Worm ₁

Affiliation

Background

Reduced levels of prostaglandin E₂ (PGE₂) contribute to aspirin-induced hypersensitivity. COX inhibitors are also frequent cofactors in anaphylaxis. Whether alterations in the PGE₂ system contribute to anaphylaxis independently of COX inhibitor intake is unclear.

Objective

Our aim was to test the hypothesis that relative PGE₂ deficiency predisposes to anaphylaxis.

Methods

Sera from 48 patients with anaphylaxis and 27 healthy subjects were analyzed for PGE₂ levels and correlated against severity; 9α,11β-PGF₂ and PGI₂ metabolites were measured for control purposes. PGE₂ stabilization by 15-hydroxyprostaglandin dehydrogenase inhibitor or EP2 or EP4 receptor agonists were used in a murine model of passive systemic anaphylaxis. FcεRI-triggered mediator release was determined in bone marrow–derived cultured mast cells (MCs) and human skin–derived MCs. Signaling was studied by Western blot analysis.

Results

Patients with anaphylaxis were characterized by markedly reduced PGE₂ levels vis-à-vis healthy subjects, whereas prostacyclin metabolite levels were diminished only weakly, and 9α,11β-PGF₂ levels conversely increased. PGE₂ was negatively correlated with severity. Lower PGE₂ levels and higher susceptibility to anaphylaxis were also found in C57BL/6 mice vis-à-vis in Balb/c mice. Stabilization of PGE₂ level by 15-hydroxyprostaglandin dehydrogenase inhibitor protected mice against anaphylaxis. Exogenous PGE₂ attenuated bone marrow–derived cultured MC activation through EP2 and EP4 receptors. EP2 and EP4 agonism also curbed FcεRI-mediated degranulation of human MCs. Mechanistically, PGE₂ interfered with the phosphorylation of phospholipase C gamma-1 and extracellular signal–regulated kinase.

Conclusions

Homeostatic levels of PGE₂ attenuate MC activation via EP2/EP4 and protect against anaphylaxis. Relative deficiency of PGE₂ predisposes to anaphylaxis in humans and mice, whereas PGE₂ stabilization protects against anaphylactic reactions.

中文翻译：

PGE2缺乏会导致肥大细胞高反应性，从而导致过敏反应。

背景

降低的前列腺素E ₂（PGE ₂）水平有助于阿司匹林引起的超敏反应。COX抑制剂也是过敏反应的常见辅助因子。目前尚不清楚PGE ₂系统的改变是否独立于COX抑制剂的摄入而导致过敏反应。

目的

我们的目的是检验相对PGE ₂缺乏易感的假说。

方法

分析了来自48名过敏反应患者和27名健康受试者的血清中PGE _2的水平，并与严重程度相关。9α，11β-PGF ₂和PGI _2种用于控制目的，测量代谢物。15-羟基前列腺素脱氢酶抑制剂或EP2或EP4受体激动剂对PGE _2的稳定作用被用于被动全身性过敏反应的小鼠模型中。FcεRI触发的介质释放是在源自骨髓的培养的肥大细胞（MC）和源自人体皮肤的MC中确定的。通过蛋白质印迹分析研究信号传导。

结果

通过显着减少PGE患者过敏性反应进行了表征₂水平VIS-à-VIS健康受试者，而前列环素代谢物水平均减弱只有弱，和9α，11β-PGF ₂水平反过来增加。PGE ₂与严重程度呈负相关。与Balb / c小鼠相比，C57BL / 6小鼠中还发现较低的PGE ₂水平和较高的过敏反应敏感性。15-羟基前列腺素脱氢酶抑制剂稳定PGE ₂水平可保护小鼠免于过敏反应。外源PGE ₂通过EP2和EP4受体减弱了源自骨髓的培养MC激活。EP2和EP4激动剂还可以抑制FcεRI介导的人MC脱粒。从机理上讲，PGE ₂干扰磷脂酶C gamma-1和细胞外信号调节激酶的磷酸化。