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 transcriptions.
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 H(1) 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.
Shahriar
Masum
M
Department of Molecular Pharmacology, Institute of Health-Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Mizuguchi
Hiroyuki
H
Maeyama
Kazutaka
K
Kitamura
Yoshiaki
Y
Orimoto
Naoki
N
Horio
Shuhei
S
Umehara
Hayato
H
Hattori
Masashi
M
Takeda
Noriaki
N
Fukui
Hiroyuki
H
D000818:Animals; D001190:Arylsulfonates / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D006367:HeLa Cells; D006632:Histamine / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000235:genetics*; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011969:Receptors, Histamine H1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013452:Sulfonium Compounds / Q000494:pharmacology*; D014051:Toluene 2,4-Diisocyanate; D014158:Transcription, Genetic
D001190:Arylsulfonates; D012333:RNA, Messenger; D011969:Receptors, Histamine H1; D013452:Sulfonium Compounds; D014051:Toluene 2,4-Diisocyanate; D015847:Interleukin-4; D006632:Histamine; C073028:suplatast tosilate; D006640:Histidine Decarboxylase