Gambogenic acid suppresses T cell proliferation via inhibition of ERK signaling pathway.

Abstract

BACKGROUND AND PURPOSE: Recent studies have highlighted the therapeutic potential of monomers derived from traditional Chinese medicine (TCM) in autoimmune diseases. Through screening, we identified the TCM monomer Gambogenic acid as demonstrating potent immunosuppressive activity. This study elucidates the mechanism of GNA in suppressing T cell proliferation in vitro and evaluates its efficacy against imiquimod (IMQ)-induced psoriasis-like dermatitis. EXPERIMENTAL APPROACH: T cell toxicity, apoptosis, CD25 expression, and cell cycle distribution were analyzed via flow cytometry. Cytokine levels were quantified by ELISA, and phosphorylation of signaling molecules was assessed by Western blot. A BALB/c mouse model of IMQ-induced psoriasis-like dermatitis was employed for in vivo evaluation. RESULTS: GNA dose-dependently inhibited anti-CD3/CD28 mAb-stimulated human T cell proliferation (P&#xa0;<&#xa0;0.01) without cytotoxicity. It suppressed CD25 expression and secretion of pro-inflammatory cytokines (IL-2, IL-6, IFN-&#x3b3;, IL-17A; P&#xa0;<&#xa0;0.05) and induced G0/G1 phase arrest in activated T cells. Mechanistically, GNA selectively blocked ERK phosphorylation (P&#xa0;<&#xa0;0.01) without affecting GSK-3&#x3b2;, NF-&#x3ba;B, or p38 MAPK signaling. In vivo, GNA significantly ameliorated IMQ-induced psoriatic lesions, reducing epidermal hyperplasia and inflammatory infiltration (P&#xa0;<&#xa0;0.01). CONCLUSIONS AND IMPLICATIONS: Our findings demonstrate that GNA inhibits T cell activation by targeting ERK signaling, highlighting its potential as a TCM-derived immunosuppressive monomer for preventing organ transplant rejection and treating autoimmune diseases. This study provides a foundation for developing GNA-based therapies.