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首页> 外文期刊>RSC Advances >Molecular mechanism of action of K(D)PT as an IL-1RI antagonist for the treatment of rhinitis
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Molecular mechanism of action of K(D)PT as an IL-1RI antagonist for the treatment of rhinitis

机译：K（D）PT作为IL-1RI拮抗剂治疗鼻炎的分子机制

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Background: Interleukin-1 receptor type I (IL-1RI) is critical for both innate immunity and inflammation. IL1-RI stimulates thymocyte proliferation and the release of several interleukin cytokines. These properties have increased interest in targeting IL-1RI for the treatment of inflammatory diseases. Here, an IL-1RI antagonist, K(D) PT (Lys-D-Pro-Thr), was tested in an allergic rhinitis model. The mechanism of action was then investigated. Methods: HEK293/IL-1RI cells and an allergic rhinitis animal model were treated with K(D) PT to evaluate its therapeutic effects. Fifty nanosecond (ns) molecular dynamic (MD) simulations were performed on the K(D) PT/IL-1RI complex, unliganded IL-1RI, and the IL-1 beta/IL-1RI complex to explore the mechanism of action of K(D) PT. Results: K(D) PT down-regulated the IL-1RI-mediated induction of IL-2 and IL-4 mRNA expression by IL-1 beta in HEK293/IL-1RI cells. In addition, nose itching was alleviated in mice treated with K(D) PT. Serum levels of IL-2 and IL-4 as well as eosinophil infiltration were also reduced. The data suggested that IL-1RI was highly expressed in the nasal mucosa of mice with allergic rhinitis. MD simulations revealed the following: (1) IL-1RI remains in the open conformation in the IL-1RI/IL-1 beta complex; (2) in unliganded IL-1RI, domains I and III randomly moved closer and apart without any significant energetic changes; (3) K(D) PT locks the C-and N- terminals of IL-1RI by forming hydrogen bonds with both terminals to adopt a closed conformation and consequently minimizes the system energy. Conclusions: IL-1RI antagonist K(D) PT effectively treated allergic rhinitis. The molecular mechanism of action indicated that K(D) PT connects the C-and N- terminals of IL-1RI via hydrogen bond formation to establish a stable conformation and consequently minimize the system energy of IL-1RI.
机译：背景：I型白介素-1受体（IL-1RI）对于先天免疫和炎症均至关重要。 IL1-RI刺激胸腺细胞增殖和几种白介素细胞因子的释放。这些特性对靶向IL-1RI治疗炎性疾病的兴趣日益浓厚。在此，在变应性鼻炎模型中测试了IL-1RI拮抗剂K（D）PT（Lys-D-Pro-Thr）。然后研究了作用机理。方法：用K（D）PT处理HEK293 / IL-1RI细胞和变应性鼻炎动物模型以评估其治疗效果。在K（D）PT / IL-1RI复合物，未配体IL-1RI和IL-1 beta / IL-1RI复合物上进行了五十纳秒（ns）的分子动力学（MD）模拟，以探索K的作用机理（D）PT。结果：K（D）PT下调了HEK293 / IL-1RI细胞中IL-1 beta对IL-1RI介导的IL-2和IL-4 mRNA表达的诱导。此外，用K（D）PT治疗的小鼠鼻子瘙痒得到缓解。血清IL-2和IL-4水平以及嗜酸性粒细胞浸润也降低了。数据表明IL-1RI在变应性鼻炎小鼠的鼻粘膜中高表达。 MD模拟显示以下：（1）IL-1RI保持在IL-1RI /IL-1β复合物中的开放构象; （2）在未配体的IL-1RI中，结构域I和III随机靠近和分开而没有任何明显的能量变化; （3）K（D）PT通过与两个末端形成氢键来锁定IL-1RI的C和N末端，从而采用闭合构象，从而最大程度地降低了系统能量。结论：IL-1RI拮抗剂K（D）PT可有效治疗变应性鼻炎。作用的分子机理表明，K（D）PT通过氢键形成连接IL-1RI的C-和N-端，以建立稳定的构象，从而使IL-1RI的系统能量最小。

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