18β-Glycyrrhetinic acid, the major bioactive component of Glycyrrhizae Radix, attenuates airway inflammation by modulating Th2 cytokines, GATA-3, STAT6, and Foxp3 transcription factors in an asthmatic mouse model

Environ Toxicol Pharmacol. 2017 Jun:52:99-113. doi: 10.1016/j.etap.2017.03.011. Epub 2017 Mar 20.

Abstract

18β-Glycyrrhetinic acid (18Gly), the major bioactive component of Glycyrrhizae Radix, possesses anti-ulcerative, anti-inflammatory, and other pharmacological properties. Although 18Gly is associated with immunoregulatory functions of allergic diseases, the pathophysiological mechanisms of 18Gly action in allergic inflammatory lung disease have not been examined. Moreover, there are no in vivo studies on the anti-asthmatic effects of 18Gly in allergic asthma. We investigated its effect and mechanism of action in airway inflammation in a BALB/c mouse model of allergic asthma. Interestingly, 18Gly strongly suppressed airway hyperresponsiveness, accumulation of inflammatory cells, and levels of T helper type 2 (Th2) cytokines (interleukin (IL)-5 and IL-13) in bronchoalveolar lavage fluid (BALF). It also attenuated lung IL-5, IL-13, and IL-4 expression, but it upregulated peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression in lungs. Moreover, it exerted immunomodulatory effects by suppressing Th2 cytokines (IL-5, IL-13) production through upregulation of forkhead box p3 (Foxp3), and downregulation of signal transducer and activator of transcription (STAT6), GATA-binding protein 3 (GATA-3), and retinoic acid-related orphan receptor γ t (RORγt) expression. These results suggest that the anti-asthmatic activity of 18Gly may occur by the suppression of IL-5, IL-13, and OVA-specific Immunoglobulin E (IgE) production through inhibition of the RORγt, STAT6, GATA-3 pathways and upregulation of the Foxp3 transcription pathway. Also, 18Gly treatment was protective against the oxidative stress by inducing significant decrease of reactive oxygen species (ROS) generation in MH-S alveolar macrophage cells. Our results suggest that 18Gly can improve allergic asthma and can be a novel therapeutic component for the treatment of allergic asthma.

Keywords: 18β-glycyrrhetinic acid; Asthma; Foxp3; GATA-3; IL-13; IL-5.

MeSH terms

  • Allergens
  • Animals
  • Anti-Asthmatic Agents / pharmacology*
  • Anti-Asthmatic Agents / therapeutic use*
  • Asthma / blood
  • Asthma / drug therapy*
  • Asthma / immunology
  • Asthma / pathology
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Cell Count
  • Cell Line
  • Cell Survival / drug effects
  • Cytokines / immunology
  • Fabaceae
  • Female
  • Forkhead Transcription Factors / immunology
  • GATA3 Transcription Factor / immunology
  • Glycyrrhetinic Acid / analogs & derivatives*
  • Glycyrrhetinic Acid / pharmacology
  • Glycyrrhetinic Acid / therapeutic use
  • Immunoglobulin E / blood
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Mice, Inbred BALB C
  • Ovalbumin
  • Phytotherapy
  • Reactive Oxygen Species / metabolism
  • STAT6 Transcription Factor / immunology
  • Spleen / cytology
  • Spleen / immunology
  • Th2 Cells / immunology

Substances

  • Allergens
  • Anti-Asthmatic Agents
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Reactive Oxygen Species
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • 18alpha-glycyrrhetinic acid
  • Immunoglobulin E
  • Ovalbumin
  • Glycyrrhetinic Acid