The cytokine interleukin-33 mediates anaphylactic shock (Retracted article. See vol. 109, pg. 15527, 2012)
The cytokine interleukin-33 mediates anaphylactic shock (Retracted article. See vol. 109, pg. 15527, 2012)
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DOI：
10.1073/pnas.0901206106
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发表时间：
2009-06-16
影响因子：
11.1
通讯作者：
Melendez, Alirio J.
中科院分区：
文献类型：
--
作者：
Pushparaj, Peter N.;Tay, Hwee Kee;Melendez, Alirio J.
过敏性休克的特征是免疫球蛋白E（IgE）抗体升高，通过高亲和力Fc ε受体（Fc ε RI）发出信号，释放炎症介质。在这里，我们报告说，新的细胞因子白细胞介素-33（IL-33）强效诱导小鼠过敏性休克，并与人类的症状。IL-33是IL-1家族的新成员，是孤儿受体ST 2的配体。在人类中，在过敏性休克期间，IL-33的水平在特应性患者的血液中以及在特应性皮炎患者的发炎皮肤组织中显著升高。在小鼠实验性特应性模型中，IL-33以T细胞非依赖性、肥大细胞依赖性方式诱导抗原非依赖性被动皮肤和全身过敏反应。在体外，IL-33直接诱导IgE致敏的肥大细胞的脱粒，强类花生酸和细胞因子的产生。触发这些反应的分子机制包括激活磷脂酶D1和鞘氨醇激酶1以介导钙动员、核因子-kappa B激活、细胞因子和类二十烷酸分泌以及脱颗粒。因此，本报告揭示了IL-33迄今未被认识到的病理生理作用，并表明IL-33可能是过敏反应的潜在治疗靶点，过敏反应是一种医疗需求尚未得到满足的疾病。
Anaphylactic shock is characterized by elevated immunoglobulin-E (IgE) antibodies that signal via the high affinity Fc epsilon receptor (Fc epsilon RI) to release inflammatory mediators. Here we report that the novel cytokine interleukin-33 (IL-33) potently induces anaphylactic shock in mice and is associated with the symptom in humans. IL-33 is a new member of the IL-1 family and the ligand for the orphan receptor ST2. In humans, the levels of IL-33 are substantially elevated in the blood of atopic patients during anaphylactic shock, and in inflamed skin tissue of atopic dermatitis patients. In murine experimental atopic models, IL-33 induced antigen-independent passive cutaneous and systemic anaphylaxis, in a T cell-independent, mast cell-dependent manner. In vitro, IL-33 directly induced degranulation, strong eicosanoid and cytokine production in IgE-sensitized mast cells. The molecular mechanisms triggering these responses include the activation of phospholipase D1 and sphingosine kinase1 to mediate calcium mobilization, Nuclear factor-kappa B activation, cytokine and eicosanoid secretion, and degranulation. This report therefore reveals a hitherto unrecognized pathophysiological role of IL-33 and suggests that IL-33 may be a potential therapeutic target for anaphylaxis, a disease of considerable unmet medical need.