title: 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.
abstract: 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.
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan. Electronic address: guchi003@tokushima-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan; Taiho Pharmaceutical Co. LTD., 224-2, Ebisuno Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Orimoto
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kadota
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kominami
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Asish K
authors.initials: AK
authors.lastname: Das
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Akiho
authors.initials: A
authors.lastname: Sawada
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Tamada
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyagi
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Adachi
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Department of Otolaryngology, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Department of Otolaryngology, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Takeda
authors.affiliation: Department of Molecular Studies for Incurable Diseases, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001190:Arylsulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D019703:Calcineurin / Q000502:physiology; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006967:Hypersensitivity / Q000188:drug therapy* / Q000235:genetics; D016906:Interleukin-9 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000502:physiology; D009668:Nose Diseases / Q000188:drug therapy* / Q000235:genetics; D051381:Rats; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013452:Sulfonium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D014051:Toluene 2,4-Diisocyanate / Q000633:toxicity*
chemical_list: D018926:Anti-Allergic Agents; D001190:Arylsulfonates; D006633:Histamine Antagonists; D016906:Interleukin-9; D050778:NFATC Transcription Factors; D011969:Receptors, Histamine H1; D013452:Sulfonium Compounds; D014051:Toluene 2,4-Diisocyanate; C073028:suplatast tosilate; D019703:Calcineurin
keywords: Antihistamines; Calcineurin/NFAT signaling; Combination therapy; PKCδ signaling; Suplatast tosilate