RATIONALE Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 (orosomucoid-like 3) expression. The locus influences disease severity and the frequency of human rhinovirus (HRV)-initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase, but its role in inflammation is incompletely understood. OBJECTIVES To investigate the role of ORMDL3 in cellular inflammation. METHODS We modeled a time series of IL1B-induced inflammation in A549 cells, using cytokine production as outputs and testing effects of ORMDL3 siRNA knockdown, ORMDL3 overexpression, and the serine palmitoyltransferase inhibitor myriocin. We replicated selected findings in normal human bronchial epithelial cells. Cytokine and metabolite levels were analyzed by analysis of variance. Transcript abundances were analyzed by group means parameterization, controlling the false discovery rate below 0.05. MEASUREMENTS AND MAIN RESULTS Silencing ORMDL3 led to steroid-independent reduction of IL6 and IL8 release and reduced endoplasmic reticulum stress after IL1B stimulation. Overexpression and myriocin conversely augmented cytokine release. Knockdown reduced expression of genes regulating host-pathogen interactions, stress responses, and ubiquitination: in particular, ORMDL3 knockdown strongly reduced expression of the HRV receptor ICAM1. Silencing led to changes in levels of transcripts and metabolites integral to glycolysis. Increased levels of ceramides and the immune mediator sphingosine-1-phosphate were also observed. CONCLUSIONS The results show ORMDL3 has pleiotropic effects during cellular inflammation, consistent with its substantial genetic influence on childhood asthma. Actions on ICAM1 provide a mechanism for the locus to confer susceptibility to HRV-induced asthma.

中文翻译：

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ORMDL3 哮喘基因调节 ICAM1 并对细胞炎症具有多重影响。

基本原理 染色体 17q21 上的多态性赋予儿童期哮喘的主要遗传易感性。风险等位基因与 ORMDL3（类粘蛋白 3）表达呈正相关。该基因座影响疾病的严重程度和人类鼻病毒 (HRV) 引发的恶化的频率。已知 ORMDL3 通过结合丝氨酸棕榈酰转移酶调节鞘脂合成，但其在炎症中的作用尚不完全清楚。目的探讨ORMDL3在细胞炎症中的作用。方法我们模拟了 A549 细胞中 IL1B 诱导的炎症的时间序列，使用细胞因子产生作为输出，并测试 ORMDL3 siRNA 敲低、ORMDL3 过表达和丝氨酸棕榈酰转移酶抑制剂 myriocin 的效果。我们在正常人支气管上皮细胞中复制了选定的发现。通过方差分析分析细胞因子和代谢物水平。通过组均值参数化分析转录本丰度，将错误发现率控制在 0.05 以下。测量和主要结果沉默 ORMDL3 导致 IL6 和 IL8 释放的类固醇独立减少，并减少 IL1B 刺激后的内质网应激。过表达和 myriocin 反过来增加细胞因子的释放。敲低降低了调节宿主-病原体相互作用、应激反应和泛素化的基因的表达：特别是，ORMDL3 敲低大大降低了 HRV 受体 ICAM1 的表达。沉默导致与糖酵解有关的转录物和代谢物水平发生变化。还观察到神经酰胺和免疫介质 1-磷酸鞘氨醇水平增加。结论 结果显示 ORMDL3 在细胞炎症期间具有多效性，与其对儿童哮喘的实质性遗传影响一致。对 ICAM1 的作用为该基因座提供了一种机制，以赋予其对 HRV 诱发的哮喘的易感性。