IL-9 and its receptor are predominantly involved in the pathogenesis of UC
IL-9 and its receptor are predominantly involved in the pathogenesis of UC
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DOI：
10.1136/gutjnl-2013-305947
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发表时间：
2015-05-01
期刊：
影响因子：
24.5
通讯作者：
Mudter, Jonas
中科院分区：
文献类型：
--
作者：
Nalleweg, Nancy;Chiriac, Mircea Teodor;Mudter, Jonas
目的在过去的二十年中，T辅助细胞(Th)1或Th2细胞的几种致病作用越来越多地与IL-17和最近的IL-9信号联系在一起。然而，到目前为止，IL-9在IBD中的意义还没有得到解决。设计我们通过采集外周血、活检组织和手术标本来研究IL-9和IL-9R的表达。我们通过对下游效应蛋白的分析来阐述IL-9信号的功能作用。用Caco-2细胞单层观察IL-9对创面愈合的影响。结果UC患者炎症组织中IL-9的表达明显高于对照组。CD3+T细胞是表达IL-9的主要细胞，部分中性粒细胞(PMN)也表达IL-9。IL-9与关键的Th9转录因子干扰素调节因子4和PU.1共定位。系统地讲，IL-9由激活的外周血淋巴细胞大量产生，而其受体在肠道滞留和循环中的PMN上过度表达。后者对IL-9的刺激以剂量依赖的方式诱导IL-8的产生，并使PMN对凋亡产生抵抗，提示IL-9R信号在肠道炎症的传播中具有功能作用。此外，IL-9R在肠上皮细胞上高表达，IL-9可诱导肠上皮细胞中STAT5的激活。结论IL-9参与了UC的发病机制，提示IL-9靶向治疗UC可能成为治疗UC的一种选择。
Objective Several pathogenic roles attributed over the past two decades to either T helper (Th) 1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far.Design We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing.Results IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3(+) T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments.Conclusions Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.