カルシニューリン/NFATシグナルにおけるピロガロールの作用機構

• Published in: 日本薬理学会年会要旨集 p. 1-O-005
• Main Authors: 水口, 博之, 中野, 友寛, 西田, 浩平, 伊藤, 智平, 湧川, 朝治, 神沼, 修, 北村, 紀子, 石田, 達也, 籔本, 雅巳, 北村, 嘉章, 武田, 憲昭, 福井, 裕行
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2020
• Subjects: allergy; signal transduction
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.93.0_1-O-005

Calcineurin-NFAT (CN/NFAT) signaling is one of the most well-known signaling pathways involving many biological functions. We have demonstrated that CN/NFAT signaling was responsible for the pathogenesis of allergic rhinitis and identified pyrogallol as an anti-allergic compound. Pyrogallol suppressed NFAT dephosphorylation and CN/NFAT signaling-mediated IL-9 gene up-regulation in RBL-2H3 cells. Pyrogallol improved toluene-2,4-diisocyanate (TDI)-induced nasal symptoms in TDI-sensitized allergy model rats. Here, we investigated the mechanism of action of pyrogallol for CN-NFAT signaling. Pyrogallol inhibited ionomycin-induced dephosphorylation and nuclear translocation of NFAT. Pull-down assay revealed that pyrogallol strengthened interaction between NFATc1 and calcineurin. Further studies demonstrated that calcineurin binding site 2 in NFATc1 was involved in pyrogallol's effect. Poly(U)-binding-splicing factor 60 (PUF60) was identified as NFATc2 binding protein using pyrogallol-immobilized affinity chromatography. Pyrogallol suppressed ionomycin-induced interaction of PUF60 with NFATc2. Knockout of PUF60 gene suppressed ionomycin-induced IL-9 gene up-regulation in RBL-2H3 cells. These results suggest that pyrogallol suppressed CN/NFAT signaling through the inhibition of NFAT dephosphorylation by the isoform-dependent manner.