Suplatast tosilate alleviates nasal symptoms through the suppression of nuclear factor of activated T-cells-mediated IL-9 gene expression in toluene-2,4-diisocyanate-sensitized rats

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• 作者：Hiroyuki Mizuguchi^a ; ^{guchi003@tokushima-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Naoki Orimoto^a ; ^b ; Takuya Kadota^a ; Takahiro Kominami^a ; Asish K. Das^a ; ¹ ; Akiho Sawada^a ; Misaki Tamada^a ; Kohei Miyagi^a ; Tsubasa Adachi^a ; Mayumi Matsumoto^a ; Tomoya Kosaka^a ; Yoshiaki Kitamura^c ; Noriaki Takeda^c ; Hiroyuki Fukui^d
• 关键词：Antihistamines ; Calcineurin/NFAT signaling ; Combination therapy ; PKCδ signaling ; Suplatast tosilate
• 刊名：Journal of Pharmacological Sciences
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：130
• 期：3
• 页码：151-158
• 全文大小：1002 K

文摘

Histamine H₁ receptor (H1R) gene is upregulated in patients with pollinosis; its expression level is highly correlated with the nasal symptom severity. Antihistamines are widely used as allergy treatments because they inhibit histamine signaling by blocking H1R or suppressing H1R signaling as inverse agonists. However, long-term treatment with antihistamines does not completely resolve toluene-2,4-diisocyanate (TDI)-induced nasal symptoms, although it can decrease H1R gene expression to the basal level, suggesting additional signaling is responsible for the pathogenesis of the allergic symptoms. Here, we show that treatment with suplatast tosilate in combination with antihistamines markedly alleviates nasal symptoms in TDI-sensitized rats. Suplatast suppressed TDI-induced upregulation of IL-9 gene expression. Suplatast also suppressed ionomycin/phorbol-12-myristate-13-acetate-induced upregulation of IL-2 gene expression in Jurkat cells, in which calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling is known to be involved. Immunoblot analysis demonstrated that suplatast inhibited binding of NFAT to DNA. Furthermore, suplatast suppressed ionomycin-induced IL-9 mRNA upregulation in RBL-2H3 cells, in which CN/NFAT signaling is also involved. These data suggest that suplatast suppressed NFAT-mediated IL-9 gene expression in TDI-sensitized rats and this might be the underlying mechanism of the therapeutic effects of combined therapy of suplatast with antihistamine.