RESUMO
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.
Assuntos
Antialérgicos/farmacologia , Sulfonatos de Arila/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Hipersensibilidade/tratamento farmacológico , Interleucina-9/genética , Fatores de Transcrição NFATC/genética , Doenças Nasais/tratamento farmacológico , Compostos de Sulfônio/farmacologia , Tolueno 2,4-Di-Isocianato/toxicidade , Animais , Antialérgicos/uso terapêutico , Sulfonatos de Arila/uso terapêutico , Calcineurina/fisiologia , Células Cultivadas , Quimioterapia Combinada , Expressão Gênica/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/uso terapêutico , Hipersensibilidade/genética , Interleucina-9/metabolismo , Masculino , Fatores de Transcrição NFATC/fisiologia , Doenças Nasais/genética , Ratos , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos de Sulfônio/uso terapêuticoRESUMO
Kujin, the dried root of Sophorae flavescensis, has been used in Chinese folklore medicine against allergy. Evaluation of its anti-allergic potential as well as its mechanism of action has rarely been established. We investigated the effect of Kujin on toluene-2,4-diisocyanate (TDI)-induced allergic behavior and related histamine signaling including mRNA levels of histamine H(1) receptor (H1R) and histidine decarboxylase (HDC), H1R and HDC activities, and histamine content in rat nasal mucosa. We also investigated the effect of Kujin on the mRNA levels of helper T cell type 2 (Th2)-cytokine genes closely related to histamine signaling. TDI provocation caused acute allergic symptoms accompanied with up-regulations of H1R and HDC mRNAs and increases in HDC activity, histamine content, and [(3)H]mepyramine binding activity in the nasal mucosa, all of which were significantly suppressed by pretreatment with Kujin for 3 weeks. Kujin also suppressed the TDI-induced IL-4 and IL-5 mRNA elevations. These data suggest that oral administration of Kujin showed anti-allergic activity through suppression of histamine signaling by the inhibition of TDI-induced H1R and HDC mRNA elevations followed by decrease in H1R, HDC protein level, and histamine content in the nasal mucosa of TDI-sensitized rats. Suppression of Th2-cytokine signaling by Kujin also suggests that it could affect the histamine-cytokine network.
