β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-Ⅰ and IFN/STAT signaling

• 作者: Bei-xian Zhou Hai-ming Jiang Jing Li Nan-shan Zhong Pei-fang Xie Xi-ping Pan Xiao-li Liang Yan-bing Hao Zi-feng Yang
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2020,（9）
• 所属期刊栏目: Pulmonary and Gastrointestinal Pharmacology
• 页码范围: 1178-1196
• 页数: 19页
• 语种: 英文

摘要

β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity.In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms.We demonstrate that β-sitosterol (150-450 μg/mL) dosedependently suppresses inflammatory response through NF-KB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells,which was accompanied by decreased induction of interferons (IFNs) (including Type Ⅰ and Ⅲ IFN).Furthermore,we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acidinducible gene Ⅰ (RIG-Ⅰ) signaling,led to decreased STAT1 signaling,thus affecting the transcriptional activity of ISGF3 (interferonstimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells.Moreover,β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors.In a mouse model of influenza,pre-administration of β-sitosterol (50,200 mg·kg-1·d-1,i.g.,for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation.In addition,pre-administration of β-sitosterol protected mice from lethal IAV infection.Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production,providing a potential benefit for the treatment of influenza.