β-sitosterol targets glucocorticoid receptor to reduce airway inflammation and remodeling in allergic asthma

• DOI: 10.1016/j.pupt.2022.102183
• Publication Date: 2022-12-06T01:44:29Z
• Authors: Jianfeng Xu; Lei Yang; Tiantian Lin
• Keywords: Inflammation; 0301 basic medicine; Mice, Inbred BALB C; Ovalbumin; Sitosterols; Asthma; 3. Good health; Molecular Docking Simulation; Transforming Growth Factor beta1; Mice; Disease Models, Animal; Mifepristone; 03 medical and health sciences; Receptors, Glucocorticoid; Animals; Humans; Airway Remodeling; Collagen; Lung

In most asthma patients, symptoms are controlled by treatment with glucocorticoid, but long-term or high-dose use can produce adverse effects. Therefore, it is crucial to find new therapeutic strategies. β-sitosterol could suppress type Ⅱ inflammation in ovalbumin (OVA)-induced mice, but its mechanisms have remained unclear.A binding activity of β-sitosterol with glucocorticoid receptor (GR) was analyzed by molecular docking. Human bronchial epithelial cells (BEAS-2B) and human bronchial smooth muscle cells (HBSMC) were treated with different concentrations (0, 1, 5, 10, 20, and 50 μg/mL) of β-sitosterol for suitable concentration selection. In transforming growth factor (TGF)-β1 treated BEAS-2B and HBSMC, cells were treated with 20 μg/mL β-sitosterol or dexamethasone (Dex) to analyze its possible mechanism. In OVA-induced mice, 2.5 mg/kg β-sitosterol or Dex administration was performed to analyze the therapeutic mechanism of β-sitosterol. A GR antagonist RU486 was used to confirm the mechanism of β-sitosterol in the treatment of asthma.A good binding of β-sitosterol to GR (score = -8.2 kcal/mol) was found, and the GR expression was upregulated with β-sitosterol dose increase in BEAS-2B and HBSMC. Interleukin (IL)-25 and IL-33 secretion was significantly decreased by β-sitosterol in the TGF-β1-induced BEAS-2B, and the levels of collagen 1A and α-smooth muscle actin (SMA) were reduced in the TGF-β1-induced HBSMC. In the OVA-challenged mice, β-sitosterol treatment improved airway inflammation and remodeling through suppressing type Ⅱ immune response and collagen deposition. The therapeutic effects of β-sitosterol were similar to Dex treatment in vitro and in vivo. RU486 treatment clearly hampered the therapeutic effects of β-sitosterol in the TGF-β1-induced cells and OVA-induced mice.This study identified that β-sitosterol binds GR to perform its functions in asthma treatment. β-sitosterol represent a potential therapeutic drug for allergic asthma.