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

• Published in: Journal of pharmacological sciences Vol. 130; no. 3; pp. 151 - 158
• Main Authors: Mizuguchi, Hiroyuki, Orimoto, Naoki, Kadota, Takuya, Kominami, Takahiro, Das, Asish K., Sawada, Akiho, Tamada, Misaki, Miyagi, Kohei, Adachi, Tsubasa, Matsumoto, Mayumi, Kosaka, Tomoya, Kitamura, Yoshiaki, Takeda, Noriaki, Fukui, Hiroyuki
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 01.03.2016; Elsevier
• Subjects: Animals; Anti-Allergic Agents - pharmacology; Anti-Allergic Agents - therapeutic use; Antihistamines; Arylsulfonates - pharmacology; Arylsulfonates - therapeutic use; Calcineurin - physiology; Calcineurin/NFAT signaling; Cells, Cultured; Combination therapy; Drug Therapy, Combination; Gene Expression - drug effects; Histamine Antagonists - pharmacology; Histamine Antagonists - therapeutic use; Hypersensitivity - drug therapy; Hypersensitivity - genetics; Interleukin-9 - genetics; Interleukin-9 - metabolism; Male; NFATC Transcription Factors - genetics; NFATC Transcription Factors - physiology; Nose Diseases - drug therapy; Nose Diseases - genetics; PKCδ signaling; Rats; Receptors, Histamine H1 - genetics; Receptors, Histamine H1 - metabolism; Signal Transduction - drug effects; Sulfonium Compounds - pharmacology; Sulfonium Compounds - therapeutic use; Suplatast tosilate; Toluene 2,4-Diisocyanate - toxicity; PKCδ signaling; Antihistamines; Calcineurin/NFAT signaling; Suplatast tosilate; Combination therapy
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2015.12.008

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.