Role of Nuclear Factor of Activated T Cells Signaling in the Development of Allergic Rhinitis

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  • アレルギー性鼻炎におけるNFATシグナルの役割とその制御
  • アレルギーセイ ビエン ニ オケル NFAT シグナル ノ ヤクワリ ト ソノ セイギョ

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<p>Histamine is a major chemical mediator that induces symptoms of allergic rhinitis through binding to the histamine H1 receptor (H1R). The H1R gene is upregulated in the nasal mucosa of patients with pollinosis, and the expression level of H1R has been shown to be strongly correlated with the severity of the nasal symptoms in allergic rhinitis. However, suppression of H1R mRNA to the basal level by antihistamines alone failed to completely alleviate the nasal symptoms of allergic rhinitis, suggesting that some additional signaling may also be involved in the pathogenesis of allergic rhinitis. We showed that treatment with suplatast in combination with an antihistamine markedly alleviated the nasal symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats, an animal model of allergic rhinitis. Suplatast was shown to suppress both TDI-induced upregulation of the IL-9 gene in the nasal mucosa of TDI-sensitized rats and ionomycin-induced nuclear factor of activated T cells (NFAT) signaling-mediated IL-9 mRNA upregulation in RBL-2H3 cells. These data suggest that NFAT-mediated upregulation of IL-9 gene expression may also be involved, in addition to upregulation of H1R, in the pathogenesis of allergic rhinitis, and that suplatast suppresses NFAT-mediated signaling to alleviate the symptoms of allergic rhinitis. We then identified pyrogallol from the extract of Awa-tea, a local fermented tea, as an anti-allergic compound. Treatment with pyrogallol in combination with an antihistamine markedly alleviated the nasal symptoms in the TDI-sensitized rat model. Pyrogallol was shown to suppress both ionomycin-induced upregulation of IL-9 gene expression in RBL-2H3 cells and dephosphorylation/nuclear translocation of NFAT in BHK-21 cells. Furthermore, we isolated proanthocyanidin (LRPC) containing a gallocatechin tetramer from the extract of local Bittyu lotus root as an anti-allergic compound. Treatment with LRPC in combination with an antihistamine markedly alleviated the nasal symptoms in the TDI-sensitized rat model. LRPC was demonstrated to suppress both ionomycin-induced IL-9 mRNA upregulation in RBL-2H3 cells and TDI-induced IL-9 mRNA upregulation in the nasal mucosa of the TDI-sensitized rat model. These data suggest that both pyrogallol and LRPC suppress NFAT-mediated upregulation of IL-9 gene expression to alleviate the symptoms of allergic rhinitis. All these data further suggest that NFAT-mediated signaling could be a novel treatment target for allergic rhinitis.</p>

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