Toll-like receptor 9 signaling has anti-inflammatory effects on the early phase of Helicobacter pylori-induced gastritis
Toll-like receptor 9 signaling has anti-inflammatory effects on the early phase of Helicobacter pylori-induced gastritis
复制标题
DOI：
10.1016/j.bbrc.2012.08.080
复制
发表时间：
2012-09-28
影响因子：
3.1
通讯作者：
Arakawa, Tetsuo
中科院分区：
文献类型：
--
作者：
Otani, Koji;Tanigawa, Tetsuya;Arakawa, Tetsuo
幽门螺杆菌(Hp)诱导的胃粘膜免疫反应偏向辅助性T细胞(Th)1表型，其主要特征是辅助性T细胞产生肿瘤坏死因子(TNF)-α和干扰素(IFN)-γ。Toll样受体(Toll-like Receptor，TLRs)通过识别细菌分子在黏膜防御微生物中发挥重要作用。在TLR家族的成员中，TLR9识别细菌未甲基化的CpG DNA位点，TLR9的信号转导诱导多种细胞因子的产生，包括I型干扰素(干扰素-α/β)。我们研究了TLR9在幽门螺杆菌诱导的小鼠胃炎中的表达及其作用。幽门螺杆菌感染后，胃组织中TLR9mRNA表达增加。TLR9主要表达于胃粘膜的巨噬细胞、树突状细胞和CD3(+)细胞。在Hp感染后2个月和4个月，TLR9基因敲除(KO)小鼠的中性粒细胞浸润和肿瘤坏死因子-α(TNF-α)和干扰素-γ(IFN-γ)的表达水平均高于野生型小鼠。感染幽门螺杆菌的野生型和TLR9KO小鼠在接种幽门螺杆菌6个月后，炎症参数的这些差异消失。幽门螺杆菌感染野生型和TLR9KO小鼠的胃组织中典型的Th2细胞因子IL-4mRNA的表达没有差异。免疫后4个月，TLR9KO小鼠的干扰素-α/β基因表达水平低于野生型小鼠。给予干扰素-α可降低幽门螺杆菌感染引起的TLR9KO小鼠中性粒细胞浸润增加以及肿瘤坏死因子-α和干扰素-γ的表达水平。我们的发现提示TLR9信号在幽门螺杆菌诱导的胃炎的早期抑制中起重要作用，其机制是通过下调干扰素-α调节的Th1型细胞因子。(C)2012 Elsevier Inc.保留所有权利。
Helicobacter pylori (H. pylon)-induced immune responses in the gastric mucosa are skewed toward T helper (Th) 1 phenotype, which is characterized by predominant production of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by helper T cells. Toll-like receptors (TLRs) play an essential role in mucosal defense against microbes through the recognition of bacterial molecules. Among the members of the TLR family, TLR9 recognizes bacterial unmethylated CpG DNA sites, and signal transduction of TLR9 induces production of a variety of cytokines, including type-I IFN (IFN-alpha/beta). We investigated the expression and role of TLR9 in H. pylon-induced gastritis in mice. Expression of TLR9 mRNA in the gastric tissue increased after infection with H. pylori. TLR9 was mainly expressed in the macrophages, dendritic cells, and CD3(+) cells in the gastric mucosa. Neutrophil infiltration and the expression levels of TNF-alpha and IFN-gamma mRNA were higher in TLR9 knockout (KO) mice than in wild-type mice at 2 and 4 months after H. pylori inoculation. These differences in inflammatory parameters between H. pylori-infected wild-type and TLR9 KO mice disappeared 6 months after H. pylori inoculation. Expression of interleukin-4 mRNA, typical Th2 cytokine, in the gastric tissue did not differ between H. pylori-infected wild-type and TLR9 KO mice. Expression level of IFN-alpha/beta mRNA in the TLR9 KO mice was lower than that in wild-type mice by 4 months after inoculation. Administration of IFN-alpha reduced H. pylori infection-induced increase in neutrophil infiltration and the expression levels of TNF-alpha and IFN-gamma mRNA in TLR9 KO mice. Our findings suggest that TLR9 signaling plays important roles in the suppression of H. pylori-induced gastritis in the early phase via downregulation of Thl-type cytokines modulated by IFN-alpha. (c) 2012 Elsevier Inc. All rights reserved.