Downstream target genes of the neuropeptide S-NPSR1 pathway
Downstream target genes of the neuropeptide S-NPSR1 pathway
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DOI：
10.1093/hmg/ddl234
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Kere, Juha
中科院分区：
文献类型：
--
作者：
Vendelin, Johanna;Bruce, Sara;Kere, Juha
神经肽S（NO2）-NO2受体1（NPSR1）通路最近被认为参与了哮喘的发病机制。本研究的目的是确定NPSR1调控的下游基因靶点。基因芯片分析发现，共有104个基因显着上调和42下调后，6小时的药物治疗。通过基因本体富集分析，“细胞增殖”、“形态发生”和“免疫应答”类别是改变最多的类别。TMM微阵列数据库的比较表明，一个共同的共调节途径，其中包括JUN/FOS癌基因同源物，早期生长反应基因，核受体亚家族4成员和双特异性磷酸酶。通过定量逆转录-PCR和免疫分析证实，基质金属肽酶10（MMP 10）、INHBA（激活素A）、白细胞介素8（IL 8）和EPH受体A2（EPHA 2）4个上调基因的表达呈现显著的剂量-反应关系。免疫组化显示MMP 10和TIMP 3均在支气管上皮中强表达，哮喘痰液标本中巨噬细胞和嗜酸性粒细胞表达MMP 10。由于气道上皮重塑是慢性哮喘的一个特征，因此NPS-NPSR1信号通路上调MMP 10和TIMP 3可能与哮喘的发病机制有关。
The neuropeptide S (NPS)-NPS receptor 1 (NPSR1) pathway has recently been implicated in the pathogenesis of asthma. The purpose of this study was to identify downstream gene targets regulated by NPSR1 upon NPS stimulation. A total of 104 genes were found significantly up-regulated and 42 down-regulated by microarray analysis 6 h after NPS administration. By Gene Ontology enrichment analysis, the categories 'cell proliferation', 'morphogenesis' and 'immune response' were among the most altered. A TMM microarray database comparison suggested a common co-regulated pathway, which includes JUN/FOS oncogene homologs, early growth response genes, nuclear receptor subfamily 4 members and dual specificity phosphatases. The expression of four up-regulated genes, matrix metallopeptidase 10 (MMP10), INHBA (activin A), interleukin 8 (IL8) and EPH receptor A2 (EPHA2), exhibited a significant NPS dose-response relationship as confirmed by quantitative reverse-transcriptase-PCR and for MMP10 by immunoassay. Immunohistochemical analyses revealed that MMP10 and TIMP metallopeptidase inhibitor 3 (TIMP3) were both strongly expressed in bronchial epithelium, and macrophages and eosinophils expressed MMP10 in asthmatic sputum samples. Because remodeling of airway epithelium is a feature of chronic asthma, the up-regulation of MMP10 and TIMP3 by NPS-NPSR1 signaling may be of relevance in the pathogenesis of asthma.