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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901058v1 183/3/2133    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Shahriar, M. Articles by Fukui, H. PubMed PubMed Citation Articles by Shahriar, M. Articles by Fukui, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB 2,4-TOLUENE DIISOCYANATE HISTAMINE TOLUENE DIISOCYANATE

Suplatast Tosilate Inhibits Histamine Signaling by Direct and Indirect Down-Regulation of Histamine H₁ Receptor Gene Expression through Suppression of Histidine Decarboxylase and IL-4 Gene Transcriptions¹

Masum Shahriar^*, Hiroyuki Mizuguchi^*, Kazutaka Maeyama, Yoshiaki Kitamura, Naoki Orimoto, Shuhei Horio^*, Hayato Umehara^*, Masashi Hattori^*, Noriaki Takeda and Hiroyuki Fukui^2,*

^* Department of Molecular Pharmacology, Institute of Health-Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; Division of Pharmacology, Department of Integrated Basic Medical Science, Ehime University School of Medicine, Toon, Japan; Department of Otolaryngology, Institute of Health-Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; and Taiho Pharmaceutical, Hannou Research Center, Saitama, Japan

Allergic rhinitis (AR) is an inflammatory disorder typified by symptoms such as sneezing, congestion, and rhinorrhea. Histamine plays important roles in eliciting AR symptoms. Up-regulation of the histamine H₁ receptor (H1R) and histidine decarboxylase (HDC) mRNAs was observed in AR patients. Th2 cytokines are also involved in the pathogenesis of AR. We examined the effect of suplatast tosilate on nasal symptoms, and H1R, HDC, and IL-4 gene expression using toluene-2,4-diisocyanate (TDI)-sensitized rats and HeLa cells expressing endogenous H1R. Provocation with TDI increased nasal symptoms, HDC activity, the histamine content of nasal lavage fluid, and the expression of H1R, HDC, and IL-4 mRNAs in TDI-sensitized rats. Pretreatment with suplatast for 2 wk significantly suppressed TDI-induced nasal symptoms and elevation of H1R, HDC, and IL-4 mRNAs. Suplatast also suppressed HDC activity in the nasal mucosa and the histamine content of the nasal lavage fluid. Bilateral injection of IL-4 into the nasal cavity of normal rats up-regulated H1R mRNA, while intranasal application of histamine up-regulated IL-4 mRNA. Suplatast suppressed IL-4-induced up-regulation of H1R mRNA in HeLa cells. However, it did not inhibit histamine-induced H1R mRNA elevation. These results suggest that suplatast alleviates nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through the suppression of histamine- and IL-4-induced H1R gene expression by the inhibitions of HDC and IL-4 gene transcriptions, respectively.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was financially supported by a Grant-in Aid for Scientific Research from Japan Society for the Promotion of Science (18390167 to H.F.) and by grants from the Osaka Medical Research Foundation for Incurable Diseases and Taiho Pharmaceutical.

² Address correspondence and reprint requests to Dr. Hiroyuki Fukui, Department of Molecular Pharmacology, Institute of Health-Biosciences, The University of Tokushima Graduate School, Tokushima, 78-1 Sho-machi 1-chome, Tokushima 770-8505. E-mail address: hfukui{at}ph.tokushima-u.ac.jp

³ Abbreviations used in this paper: AR, allergic rhinitis; H1R, histamine H₁ receptor; HDC, histidine decarboxylase; rrIL-4, recombinant rat IL-4; TDI, toluene-2,4-diisocyanate.