一种化合物 DA-6034 作用于幽门螺杆菌感染胃上皮细胞中 NF-κB 通路激活的机制。

A mechanism for the action of the compound DA-6034 on NF-κB pathway activation in Helicobacter pylori-infected gastric epithelial cells.

机构信息

Department of Microbiology, Hanyang University College of Medicine, Seoul, KoreaDepartment of Biotechnology, Joongbu University, Choongnam, KoreaResearch Laboratory, Dong-A Pharmaceutical Company, Kyunggi-do, KoreaDepartment of Food and Nutrition, Yonsei University, Seoul, KoreaDepartment of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.

出版信息

Scand J Immunol. 2011 Sep;74(3):253-263. doi: 10.1111/j.1365-3083.2011.02577.x.

DOI:10.1111/j.1365-3083.2011.02577.x

PMID:21623862

Abstract

DA-6034 is a synthetic derivative of eupatilin, a flavonoid with anti-inflammatory effects. The aim of this study was to investigate the effects of DA-6034 on the interactions between IκB kinase (IKK) and heat shock protein 90 (Hsp90), and activation of the nuclear factor-kappaB (NF-κB) signalling pathway in human gastric epithelial cells infected with Helicobacter pylori. MKN-45 gastric epithelial cell line was treated with DA-6034 and H. pylori. DA-6034 significantly inhibited NF-κB activation and upregulated the expressions of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 in MKN-45 cells infected with H. pylori. However, DA-6034 did not influence activator protein-1 DNA binding activity in H. pylori-infected gastric epithelial cells. Pretreatment with DA-6034 attenuated the H. pylori-induced increase in IKK activity, and Hsp90 was associated with IKK-α and IKK-γ in MKN-45 cells. Treatment with DA-6034 dissociated the Hsp90 and IKK-γ complex in H. pylori-infected cells, leading to the inhibition of IL-8 expression. These results suggest that the eupatilin derivative 7-carboxymethyloxy-3',4',5-trimethoxy flavone has anti-inflammatory activity in gastric epithelial cells infected with H. pylori through the promotion of the dissociation of the IKK-γ-Hsp90 complex and suppression of NF-κB signalling.

摘要

DA-6034 是一种具有抗炎作用的类白杨素黄酮的合成衍生物。本研究旨在探讨 DA-6034 对人胃上皮细胞感染幽门螺杆菌时 IκB 激酶 (IKK) 和热休克蛋白 90 (Hsp90) 相互作用以及核因子-κB (NF-κB) 信号通路激活的影响。用 DA-6034 和 H. pylori 处理 MKN-45 胃上皮细胞系。DA-6034 显著抑制 NF-κB 激活，并上调 MKN-45 细胞中 H. pylori 感染的白细胞介素-8 (IL-8) 和单核细胞趋化蛋白-1 的表达。然而，DA-6034 不影响 H. pylori 感染胃上皮细胞中激活蛋白-1 DNA 结合活性。DA-6034 预处理可减弱 H. pylori 诱导的 IKK 活性增加，并且 Hsp90 与 MKN-45 细胞中的 IKK-α 和 IKK-γ 相关。在 H. pylori 感染的细胞中，DA-6034 处理可使 Hsp90 和 IKK-γ 复合物解离，从而抑制 IL-8 表达。这些结果表明，类白杨素衍生物 7-羧甲基氧基-3'，4'，5-三甲氧基黄酮通过促进 IKK-γ-Hsp90 复合物的解离和抑制 NF-κB 信号通路，在 H. pylori 感染的胃上皮细胞中具有抗炎活性。