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

ABSTRACT

INTRODUCTION: 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. ß-sitosterol could suppress type Ⅱ inflammation in ovalbumin (OVA)-induced mice, but its mechanisms have remained unclear. METHODS: A binding activity of ß-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 ß-sitosterol for suitable concentration selection. In transforming growth factor (TGF)-ß1 treated BEAS-2B and HBSMC, cells were treated with 20 µg/mL ß-sitosterol or dexamethasone (Dex) to analyze its possible mechanism. In OVA-induced mice, 2.5 mg/kg ß-sitosterol or Dex administration was performed to analyze the therapeutic mechanism of ß-sitosterol. A GR antagonist RU486 was used to confirm the mechanism of ß-sitosterol in the treatment of asthma. RESULTS: A good binding of ß-sitosterol to GR (score = -8.2 kcal/mol) was found, and the GR expression was upregulated with ß-sitosterol dose increase in BEAS-2B and HBSMC. Interleukin (IL)-25 and IL-33 secretion was significantly decreased by ß-sitosterol in the TGF-ß1-induced BEAS-2B, and the levels of collagen 1A and α-smooth muscle actin (SMA) were reduced in the TGF-ß1-induced HBSMC. In the OVA-challenged mice, ß-sitosterol treatment improved airway inflammation and remodeling through suppressing type Ⅱ immune response and collagen deposition. The therapeutic effects of ß-sitosterol were similar to Dex treatment in vitro and in vivo. RU486 treatment clearly hampered the therapeutic effects of ß-sitosterol in the TGF-ß1-induced cells and OVA-induced mice. CONCLUSION: This study identified that ß-sitosterol binds GR to perform its functions in asthma treatment. ß-sitosterol represent a potential therapeutic drug for allergic asthma.