Blanchard Carine, Mingler Melissa K, Vicario Maria, Abonia J Pablo, Wu Yi Ying, Lu Thomas X, Collins Margaret H, Putnam Philip E, Wells Susanne I, Rothenberg Marc E
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
J Allergy Clin Immunol. 2007 Dec;120(6):1292-300. doi: 10.1016/j.jaci.2007.10.024.
Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease. Early studies have established that esophageal eosinophilia occurs in association with T(H)2 allergic responses, and we recently identified an EE-specific esophageal transcriptome that included eotaxin-3.
We sought to determine the mechanism by which this T(H)2 response leads to EE.
Real-time PCR and microarray analysis were performed on RNA extracted from esophageal biopsy specimens and primary esophageal epithelial cell cultures stimulated with IL-13 (0-100 ng/mL). Transient transfections in esophageal cell lines were performed with plasmids containing the luciferase gene driven by eotaxin-3 promoter fragments and modified forms of signal transducer and activator of transcription 6.
The IL-13 mRNA level was markedly increased (16-fold) in esophageal biopsy specimens from patients with EE compared with those from healthy individuals. Furthermore, IL-13 treatment of primary esophageal epithelial cells was sufficient to induce a global-expression transcript profile that remarkably overlapped with the EE-specific esophageal transcriptome. In addition, esophageal epithelial cells markedly produce eotaxin-3 after IL-13 stimulation through a transcriptional mechanism dependent on signal transducer and activator of transcription 6. Lastly, increased IL-13 mRNA levels and the EE transcriptome were largely reversible with glucocorticoid treatment in vivo.
Taken together, we propose that the pathogenesis of EE is mediated by an IL-13-stimulated keratinocyte-derived transcriptome that is largely reversible with corticosteroid treatment. Furthermore, we identify an in vivo IL-13-induced transcriptome that has potential utility for target assessment after anti-IL-13 therapeutics.
IL-13-induced pathways and genes are fundamental processes in the cause and manifestations of EE; as such, therapeutic agents that interfere with IL-13 might be particularly useful for disease treatment.
嗜酸性粒细胞性食管炎（EE）是一种在全球范围内逐渐增多的疾病，其症状与胃食管反流病相似。早期研究已证实食管嗜酸性粒细胞增多与T(H)2型过敏反应有关，并且我们最近鉴定出了一种EE特异性的食管转录组，其中包括嗜酸性粒细胞趋化因子-3。
我们试图确定这种T(H)2反应导致EE的机制。
对从食管活检标本和用白细胞介素-13（0-100 ng/mL）刺激的原代食管上皮细胞培养物中提取的RNA进行实时PCR和微阵列分析。用含有由嗜酸性粒细胞趋化因子-3启动子片段驱动的荧光素酶基因的质粒以及信号转导和转录激活因子6的修饰形式，对食管细胞系进行瞬时转染。
与健康个体相比，EE患者食管活检标本中的白细胞介素-13 mRNA水平显著升高（16倍）。此外，用白细胞介素-13处理原代食管上皮细胞足以诱导出一种全局表达转录谱，该转录谱与EE特异性食管转录组显著重叠。另外，食管上皮细胞在白细胞介素-13刺激后通过依赖信号转导和转录激活因子6的转录机制显著产生嗜酸性粒细胞趋化因子-3。最后，在体内用糖皮质激素治疗后，白细胞介素-13 mRNA水平升高和EE转录组在很大程度上是可逆的。
综上所述，我们提出EE的发病机制是由白细胞介素-13刺激的角质形成细胞衍生的转录组介导的，而皮质类固醇治疗在很大程度上可使其逆转。此外，我们鉴定出了一种体内白细胞介素-13诱导的转录组，其在抗白细胞介素-13治疗后的靶点评估中具有潜在用途。
白细胞介素-13诱导的途径和基因是EE病因及表现中的基本过程；因此，干扰白细胞介素-13的治疗药物可能对该疾病的治疗特别有用。
