Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation
Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation
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DOI：
10.1038/ncomms9327
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发表时间：
2015-09-01
影响因子：
16.6
通讯作者：
Mustelin, Tomas
中科院分区：
文献类型：
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作者：
Cohen, E. Suzanne u;Scott, Ian C.;Mustelin, Tomas
在应对感染和刺激物时，呼吸道上皮细胞释放alarmin白细胞介素（IL）-33以引起快速的免疫反应。然而，关于IL-33释放后的调节知之甚少。在这里，我们报告说，IL-33在其受体ST 2的生物活性迅速终止在细胞外环境中形成的两个二硫桥，导致广泛的构象变化，破坏ST 2的结合位点。在来自用链格孢属提取物激发的小鼠的肺灌洗样品和来自中度-重度哮喘患者的痰中可以检测到还原（活性）和二硫键（非活性）形式的IL-33。我们认为，这种机制分泌的IL-33的快速失活构成了一个“分子钟”，限制了呼吸道刺激的ST 2依赖性免疫反应的范围和持续时间。其他IL-1家族成员也易受半胱氨酸氧化变化的影响，这可能通过类似的机制调节其活性和全身暴露。
In response to infections and irritants, the respiratory epithelium releases the alarmin interleukin (IL)-33 to elicit a rapid immune response. However, little is known about the regulation of IL-33 following its release. Here we report that the biological activity of IL-33 at its receptor ST2 is rapidly terminated in the extracellular environment by the formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site. Both reduced (active) and disulphide bonded (inactive) forms of IL-33 can be detected in lung lavage samples from mice challenged with Alternaria extract and in sputum from patients with moderate-severe asthma. We propose that this mechanism for the rapid inactivation of secreted IL-33 constitutes a 'molecular clock' that limits the range and duration of ST2-dependent immunological responses to airway stimuli. Other IL-1 family members are also susceptible to cysteine oxidation changes that could regulate their activity and systemic exposure through a similar mechanism.