Premium
Intracellular upstream signals activate histamine H 1 receptor and interleukin‐9 gene expression, sensitive to pollinosis
Author(s) -
Fukui Hiroyuki,
Mizuguchi Hiroyuki,
Kitamura Yoshiaki,
Nemoto Hisao,
Kashiwada Yoshiki,
Takeda Noriaki
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb632
Subject(s) - antihistamine , histamine , receptor , histamine h1 receptor , gene expression , messenger rna , endocrinology , medicine , pharmacology , immunology , chemistry , gene , biochemistry , antagonist
Number of pollinosis patients is increasing worldwidely. It is important for better alleviation to identify the sensitive genes of pollinosis. We observed that stimulation of histamine H 1 receptor (H1R) induces H1R up‐regulation through the protein kinase C‐delta (PKC‐delta) activation pathway. Then we hypothesized that H1R up‐regulation worsens the symptoms of pollinosis due to the increase of receptor signaling. Correlation between nasal mucosal H1R mRNA level and symptom score was demonstrated in pollinosis patients, and treatment with antihistamine resulted the normalization of mRNA elevation and alleviation of symptoms. The result suggests that H1R gene functions as a sensitive gene for pollinosis. Elevation of H1R mRNA was induced in nasal mucosa of allergic rhinitis model rats sensitized with toluene 2,4‐diisocyanete. The elevation was completely suppressed with antihistamine treatment. However, alleviation of symptoms was partial, suggesting the existence of the second gene, sensitive to pollinosis. Combination treatment of an antihistamine and Awa‐tea, a fermented tea produced in domestic area of Tokushima, Japan, was attempted. We observed that about 90% of symptom was alleviated. The result suggests that Awa‐tea contains a compound which suppresses gene expression of the second pollinosis sensitive gene. Elevation of interleukin‐9 (IL‐9) mRNA level in nasal mucosa of allergic rhinitis model rats was suppressed with Awa‐tea. IL‐9 mRNA elevation was also observed in RBL‐2H3 cells, a mast cell line, through the activation of calcineurin (CN)/NFAT signaling. The elevation was suppressed with Awa‐tea, however, not with antihistamines. An active compound was attempted to purify from Awa‐tea by monitoring suppressive activity on IL‐9 mRNA elevation, and pyrogallol was identified. Treatment with pyrogallol in combination with epinastine, an antihistamine, markedly alleviated nasal symptoms. Pyrrogallol did not inhibit protein phosphatase activity of CN. Pyrogallol suppressed ionomycin‐induced IL‐9 mRNA upregulation in RBL‐2H3 cells. Treatment with pyrogallol in combination with epinastine markedly alleviated nasal symptoms in allergic rhinitis model rats. Above results suggest that combination therapy will be effective to alleviate allergic rhinitis by suppressing both PKC‐delta and CN/NFAT signaling pathways.