ß-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.
Acta Pharmacol Sin
; 41(9): 1178-1196, 2020 Sep.
Article
in English
| MEDLINE | ID: covidwho-549299
ABSTRACT
ß-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 ß-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that ß-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 ß-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, ß-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 ß-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 ß-sitosterol protected mice from lethal IAV infection. Our data suggest that ß-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Sitosterols
/
Signal Transduction
/
Acute Lung Injury
/
DEAD Box Protein 58
/
Inflammation
Type of study:
Randomized controlled trials
Limits:
Animals
/
Female
/
Humans
Language:
English
Journal:
Acta Pharmacol Sin
Journal subject:
Pharmacology
Year:
2020
Document Type:
Article
Affiliation country:
S41401-020-0403-9
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