Daphnetin alleviates allergic airway inflammation by inhibiting T-cell activation and subsequent JAK/STAT6 signaling

• DOI: 10.1016/j.ejphar.2024.176826
• Publication Date: 2024-07-20T15:32:50Z
• Authors: Ji-Yoon Park; Jae-Won Lee; Eun Sol Oh; Yu Na Song; Myung-Ji Kang; Hyung Won Ryu; Doo-Young Kim; Sei-Ryang Oh; Juhyun Lee; Jinseon Choi; Namho Kim; Mun-Ock Kim; Sung-Tae Hong; Su Ui Lee
• Keywords: Mice, Inbred BALB C; T-Lymphocytes; Anti-Inflammatory Agents; GATA3 Transcription Factor; Lymphocyte Activation; Asthma; Cell Line; Mice; Th2 Cells; Animals; Cytokines; Female; Daphne; Calcium; Umbelliferones; STAT6 Transcription Factor; Signal Transduction; Janus Kinases

Allergic asthma is a major health burden on society as a chronic respiratory disease characterized by inflammation and muscle tightening around the airways in response to inhaled allergens. Daphne kiusiana Miquel is a medicinal plant that can suppress allergic airway inflammation; however, its specific molecular mechanisms of action are unclear. In this study, we aimed to elucidate the mechanisms by which D. kiusiana inhibits allergic airway inflammation. We evaluated the anti-inflammatory effects of the ethyl acetate (EA) fraction of D. kiusiana and its major compound, daphnetin, on murine T lymphocyte EL4 cells stimulated with phorbol 12-myristate 13-acetate and ionomycin in vitro and on asthmatic mice stimulated with ovalbumin in vivo. The EA fraction and daphnetin inhibited T-helper type 2 (Th2) cytokine secretion, serum immunoglobulin E production, mucus secretion, and inflammatory cell recruitment in vivo. In vitro, daphnetin suppressed intracellular Ca2+ mobilization (a critical regulator of nuclear factor of activated T cells) and functions of the activator protein 1 transcription factor to reduce interleukin (IL)-4 and IL-13 expression. Daphnetin effectively suppressed the IL-4/-13-induced activation of Janus kinase (JAK)/signal transducer and activator of transcription 6 (STAT6) signaling in vitro and in vivo, thereby inhibiting the expression of GATA3 and PDEF, two STAT6-target genes responsible for producing Th2 cytokines and mucins. These findings indicate that daphnetin suppresses allergic airway inflammation by stabilizing intracellular Ca2+ levels and subsequently inactivating the JAK/STAT6/GATA3/PDEF pathway, suggesting that daphnetin is a promising alternative to existing asthma treatments.