Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Osaka 545-8585, Japan.
Biochem Biophys Res Commun. 2012 Sep 28;426(3):342-9. doi: 10.1016/j.bbrc.2012.08.080. Epub 2012 Aug 24.
Helicobacter pylori (H. pylori)-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)-α and interferon (IFN)-γ 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-α/β). We investigated the expression and role of TLR9 in H. pylori-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-α and IFN-γ 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-α/β mRNA in the TLR9 KO mice was lower than that in wild-type mice by 4 months after inoculation. Administration of IFN-α reduced H. pylori infection-induced increase in neutrophil infiltration and the expression levels of TNF-α and IFN-γ 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 Th1-type cytokines modulated by IFN-α.
幽门螺杆菌（H. pylori）诱导的胃黏膜免疫应答偏向辅助性 T 细胞（Th）1 表型，其特征是辅助性 T 细胞主要产生肿瘤坏死因子（TNF）-α和干扰素（IFN）-γ。Toll 样受体（TLR）通过识别细菌分子，在黏膜防御微生物方面发挥重要作用。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 IFN（IFN-α/β）。我们研究了 TLR9 在 H. pylori 诱导的小鼠胃炎中的表达和作用。感染 H. pylori 后，胃组织中 TLR9 mRNA 的表达增加。TLR9 主要在胃黏膜中的巨噬细胞、树突状细胞和 CD3（+）细胞中表达。感染 H. pylori 2 和 4 个月后，TLR9 敲除（KO）小鼠的中性粒细胞浸润以及 TNF-α和 IFN-γ mRNA 的表达水平高于野生型小鼠。感染 H. pylori 6 个月后，H. pylori 感染野生型和 TLR9 KO 小鼠之间这些炎症参数的差异消失。胃组织中白细胞介素-4 mRNA 的表达，典型的 Th2 细胞因子，在 H. pylori 感染的野生型和 TLR9 KO 小鼠之间没有差异。感染后 4 个月，TLR9 KO 小鼠 IFN-α/β mRNA 的表达水平低于野生型小鼠。IFN-α 给药降低了 TLR9 KO 小鼠中 H. pylori 感染诱导的中性粒细胞浸润和 TNF-α和 IFN-γ mRNA 表达水平的增加。我们的研究结果表明，TLR9 信号通过下调 IFN-α 调节的 Th1 型细胞因子，在早期阶段对 H. pylori 诱导的胃炎发挥重要作用。
