Kirenol alleviates Th2-driven allergic asthma by modulating T-cell responses.

Allergic asthma is predominantly driven by type 2 T helper (Th2)-mediated immune responses. In this study, we investigated the therapeutic potential and mechanisms of kirenol (Kr) in mice with ovalbumin (OVA)-induced asthma and T-cell models. In the asthmatic mouse model, oral administration of 3 mg/kg body weight of Kr significantly alleviated OVA-specific IgE production, airway hyperresponsiveness, and levels of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL11 and CXCL1). Additionally, Kr treatment attenuated inflammatory cell recruitment and mucus production in the lungs. A reduction in the Th2-mediated immune response was observed without inducing CD4+ T cell apoptosis in Kr-treated mice. Furthermore, the mechanism of the antiallergic effect regulated by Kr was explored in an anti-CD3/CD28-stimulated CD4+ T cell model. Kr at 40 μM suppressed T-cell proliferation by arresting cell cycle progression at the G0/G1 phase. Kr decreased the secretion of IL-2 and Th2 cytokines (IL-4, IL-5, IL-10, and IL-13), while minimally affecting a Th1 cytokine (IFN-γ). Moreover, Kr inhibited Th2 polarization by downregulating expression of the Th2 master transcription factor GATA binding protein 3 (GATA3) gene and reduced T-cell activation markers (CD25, CD71, and CD134). A transcriptomic analysis revealed that Kr influenced the expression of immune-related genes that regulate cell activation, cytokine secretion, cell migration, and inflammatory responses in T cells. However, Kr had no significant immunomodulatory effect on OVA (100 μg/mL)-stimulated bone marrow-derived dendritic cells. These findings suggest that Kr effectively regulates CD4+ T cell proliferation, activation, and differentiation, highlighting its potential as a treatment for allergic asthma.