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 Jing Li Xiao-li Liang Xi-ping Pan Yan-bing Hao Pei-fang Xie Hai-ming Jiang Zi-feng Yang Nan-shan Zhong 

机构地区：[1]Department of Pharmacy,The People’s Hospital of Gaozhou,Gaozhou 525200,China [2]State Key Laboratory of Respiratory Disease,National Clinical Research Center of Respiratory Disease,Guangzhou Institute of Respiratory Health,the First Affiliated Hospital of Guangzhou Medical University,Guangzhou 510120,China [3]Institute of Combination Chinese and Western Medicine,Guangzhou Medical University,Guangzhou 511436,China [4]State Key Laboratory of Quality Research in Chinese Medicine,Macao Institute for Applied Research in Medicine and Health,Macao University of Science and Technology,Taipa,Macao,SAR,China [5]KingMed Virology Diagnostic&Translational Center,Guangzhou 510320,China

出　　处：《Acta Pharmacologica Sinica》2020年第9期1178-1196,共19页中国药理学报（英文版）

基　　金：This study was funded by the National Natural Science Foundation of China(grant no.81873065);the Secondary Development Projects of Guangdong Famous and Excellent Traditional Chinese Patent Medicines(grant no.20174005);the Natural Science Foundation of Guangdong Province(grant no.2018A030310172);the China Postdoctoral Science Foundation(grant nos.2017M622652 and 2019M652987).

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 ofβ-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms.We demonstrate thatβ-sitosterol(150–450μg/mL)dosedependently suppresses inflammatory response through NF-κB 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 ofβ-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 IFNsensitized 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 ofβ-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 ofβ-sitosterol protected mice from lethal IAV infection.Our data suggest thatβ-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production,providing a potential benefit for the treatment of influenza.

关 键 词：influenza A virus Β-SITOSTEROL RIG-I IFN-Β ANTI-INFLAMMATORY acute lung injury 

分 类 号：R96[医药卫生—药理学]