Gardenia jasminoides fruit extract alleviates MC903-induced atopic dermatitis and reduces IL-4/IL-13-induced tight junction disruption and inflammation by regulating the phosphorylation of STAT6.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Gardenia jasminoides Ellis, which belongs to the plant family Rubiaceae, was first recorded in Shennong's Herbal Medicine and has been used in traditional Chinese medicine. Pharmacological studies have shown that Gardenia has certain liver- and gallbladder-protecting, blood sugar-lowering, pancreatic secretion-promoting, gastric function-protective, blood pressure-lowering, lipid-regulating, neuroprotective, anti-inflammatory, antioxidant, anti-fatigue, and anti-thrombotic activities. Moreover, G. jasminoides fruit extract (GJFE) can ameliorate symptoms of atopic dermatitis, but the specific mechanisms involved remain unclear.

AIM OF THE STUDY: The aim of this study was to investigate the potential mechanisms and signalling pathways through which GJFE alleviates atopic dermatitis (AD) in keratinocytes, three-dimensional (3D) epidermal models and mouse models.

METHODS: We established a model of IL-4- and IL-13-induced atopic dermatitis using keratinocytes and 3D epidermal models. Additionally, an atopic dermatitis model was induced by applying MC903 (calcipotriol) to mouse ears for 8 consecutive days. The effects of GJFE and gardenoside on inflammation and skin barrier damage were verified through western blotting, quantitative polymerase chain reaction, immunofluorescence and network pharmacology. To further elucidate the molecular mechanisms involved, we employed small interfering RNA and small molecule inhibitors to investigate the relationships among OVOL1, signal transducer and activator of transcription 6 (STAT6), and tight junctions.

RESULTS: Our findings provide convincing evidence that GJFE may alleviate atopic dermatitis by inhibiting inflammation and repairing the barrier in human keratinocytes, 3D epidermal models and AD mouse model. Specifically, it was found to suppress the expression of key inflammatory cytokines and chemokines, including IL-24, IL-33, and CCL26. Simultaneously, it promoted the expression of proteins essential for preserving skin barrier integrity, such as CLDN1, CLDN4, and OVOL1. We discovered that these effects are mediated via the JAK-STAT6 signalling pathway. Furthermore, we revealed that STAT6 phosphorylation is crucial for the regulation of downstream tight junction proteins and that OVOL1 can affect the expression of CLDN1 and CLDN4.

CONCLUSION: Our study demonstrates that Gardenia jasminoides fruit extract alleviates MC903-induced atopic dermatitis and reduces IL-4/IL-13-induced tight junction disruption and inflammation by regulating the phosphorylation of STAT6. Our findings provide preliminary experimental evidence supporting the potential application value of GJFE in the treatment of atopic dermatitis, particularly in terms of its anti-inflammatory and barrier-repairing functions.