Induction and regulation of Smad7 in the gastric mucosa of patients with Helicobacter pylori infection
Induction and regulation of Smad7 in the gastric mucosa of patients with Helicobacter pylori infection
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DOI：
10.1053/j.gastro.2003.11.048
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发表时间：
2004-03-01
期刊：
影响因子：
29.4
通讯作者：
Pallone, F
中科院分区：
文献类型：
--
作者：
Monteleone, G;Blanco, GD;Pallone, F
背景与目的：幽门螺杆菌（Helicobacter pylori，Hp）感染是一种慢性胃炎，可导致消化性溃疡和癌症。炎症反应是多因素的，其特征在于过度的Th 1细胞因子产生。Th 1应答是如何在Hp感染患者的胃中诱导和维持的仍不清楚。转化生长因子（TGF）-β 1负调节Th 1细胞发育，TGF-β 1缺陷小鼠自发发生胃炎。在这里，我们研究了TGF-β 1信号在幽门螺杆菌相关性胃炎。研究方法：采用ELISA法检测Hp感染和非Hp感染患者的胃活检标本中TGF-β 1的含量，Western blotting法检测Smad 3和Smad 7的表达。在正常胃粘膜活检标本中检测干扰素（IFN）-γ对Smad 7的诱导，而在Hp定植的活检标本中分析Smad 7抑制对持续Th 1应答的影响。结果：对照组和Hp感染组胃粘膜中TGF-β 1的表达均较对照组丰富，但两组间无显著性差异。尽管如此，在整个活检标本和幽门螺杆菌感染的患者分离的粘膜细胞，有缺陷的TGF-β 1相关的Smad 3磷酸化，这是与抑制剂Smad 7的高表达。用反义寡核苷酸阻断Smad 7可恢复Hp感染患者活检标本中的TGF-β 1信号传导，同时减少干扰素-γ和T-bet。Smad 7在正常胃活检标本中可通过STAT 1依赖性机制被干扰素γ诱导，而Hp感染患者活检标本中干扰素γ的中和作用可降低Smad 7的表达。结论.这些数据表明，在Hp感染的胃粘膜，干扰素-γ诱导Smad 7的表达，然后阻止内源性TGF-β 1下调正在进行的组织损伤性Th 1反应。
Background&Aims: Helicobacter pylori (Hp) infection causes a chronic gastric inflammation, which can lead to peptic ulceration and cancer. The inflammatory response is multifactorial and is characterized by exaggerated Th1 cytokine production. How the Th1 response is induced and maintained in the stomach of Hp-infected patients remains unclear. Transforming growth factor (TGF)-beta1 negatively regulates Th1 cell development, and TGF-beta1-deficient mice spontaneously develop gastritis. Here, we examined TGF-beta1 signaling in Hp-associated gastritis. Methods: Gastric biopsy specimens taken from patients with or without Hp infection were analyzed for the content of activated TGF-beta1 by ELISA and Smad3 and 7 expression by Western blotting. Induction of Smad7 by interferon (IFN)-gamma was examined in normal gastric mucosal biopsy specimens, whereas the effect of Smad7 inhibition on the ongoing Th1 response was analyzed in Hp-colonized biopsy specimens. Results: Activated TGF-beta1 was abundant in the mucosa of controls and Hp-infected patients, with no significant difference between the 2 groups. Despite this, in whole biopsy specimens and isolated mucosal cells from Hp-infected patients, there was defective TGF-beta1-associated Smad3 phosphorylation, which was associated with high expression of the inhibitor Smad7. Blocking Smad7 with antisense oligonucleotides restored TGF-beta1 signaling in biopsy specimens from Hp-infected patients and concomitantly reduced interferon-gamma and T-bet. Smad7 was inducible in normal gastric biopsy specimens by interferon-gamma through a STAT1-dependent mechanism, and neutralization of interferon-gamma in biopsy specimens from Hp-infected patients reduced Smad7 expression. Conclusions. These data suggest that, in Hp-infected gastric mucosa, interferon-gamma induces the expression of Smad7, which then prevents endogenous TGF-beta1 from down-regulating the ongoing tissue-damaging Th1 response.