Asai, Haruka;
Kato, Koichi;
Miyasaka, Mayu;
Hatsukawa, Kaho;
Murakami, Nanami;
Takeda, Naoko;
Abe, Junna;
Aoyagi, Yutaka;
Kohda, Yuka;
Gui, Ming-Yu;
Jin, Yong-Ri;
Li, Xu-Wen;
Hitotsuyanagi, Yukio;
Takeya, Koichi;
Andoh, Tsugunobu;
Kurosaki, Hiromasa;
Fukuishi, Nobuyuki.
Artículo
en Inglés
| MEDLINE
| ID: mdl-38797160
RESUMEN
INTRODUCTION: Kamebakaurin is an active constituent of both Rabdosia japonica and Rabdosia excisa, which are utilized in Chinese traditional medicine for improving symptoms in patients with allergies. We investigated the molecular mechanisms of the anti-allergic effects of kamebakaurin using BMMCs. METHODS: The degranulation ratio, histamine release, and the interleukin (IL)-4, leukotriene B4 (LTB4), and cysteinyl leukotriene productions on antigen-triggered BMMC were investigated. Additionally, the effects of kamebakaurin on signal transduction proteins were examined by Western blot and binding to the Syk and Lyn kinase domain was calculated. The effects of kamebakaurin on antigen-induced hyperpermeability were investigated using mouse model. RESULTS: At 10 µm, kamebakaurin partially inhibited degranulation, histamine release, and IL-4 production. At 30 µm, kamebakaurin partially reduced LTB4 and cysteinyl leukotriene productions and suppressed degranulation, histamine release, and IL-4 production. Phosphorylation of both Syk Y519/520 and its downstream protein, Gab2, was reduced by kamebakaurin, and complete inhibition was observed with 30 µm kamebakaurin. In contrast, phosphorylation of Erk was only partially inhibited, even in the presence of 30 µm kamebakaurin. Syk Y519/520 is known to be auto-phosphorylated via intramolecular ATP present in its own ATP-binding site, and this auto-phosphorylation triggers degranulation, histamine release, and IL-4 production. Docking simulation study indicated kamebakaurin blocked ATP binding to the ATP-binding site in Syk. Therefore, inhibition of Syk auto-phosphorylation by kamebakaurin binding to the Syk ATP-binding site appeared to cause a reduction of histamine release and IL-4 production. Kamebakaurin inhibited antigen-induced vascular hyperpermeability in a dose-dependent fashion but did not reduce histamine-induced vascular hyperpermeability. CONCLUSION: Kamebakaurin ameliorates allergic symptoms via inhibition of Syk phosphorylation; thus, kamebakaurin could be a lead compound for the new anti-allergic drug.