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.

Abstract

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) dose-dependently 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 of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated 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.

• Authors: 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
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 41 Issue 9 Pg. 1178-1196 (Sep 2020) ISSN: 1745-7254 [Electronic] United States
• PMID: 32504068 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Interferon Type I
• STAT1 Transcription Factor
• Sitosterols
• Stat1 protein, mouse
• gamma-sitosterol
• Interferons
• Ddx58 protein, mouse
• DEAD Box Protein 58
• Interferon Lambda

Topics

• A549 Cells
• Acute Lung Injury (drug therapy, pathology, virology)
• Animals
• Antiviral Agents (analysis, therapeutic use)
• Apoptosis (drug effects)
• DEAD Box Protein 58 (metabolism)
• Dogs
• Female
• HEK293 Cells
• Humans
• Inflammation (drug therapy, pathology, virology)
• Influenza A Virus, H1N1 Subtype (drug effects)
• Interferon Type I (metabolism)
• Interferons (metabolism)
• Lung (pathology)
• Madin Darby Canine Kidney Cells
• Mice, Inbred BALB C
• Plants (chemistry)
• STAT1 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Sitosterols (analysis, therapeutic use)
• Interferon Lambda