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
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
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DOI：
10.4049/jimmunol.0901058
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发表时间：
2009-08-01
影响因子：
4.4
通讯作者：
Fukui, Hiroyuki
中科院分区：
文献类型：
--
作者：
Shahriar, Masum;Mizuguchi, Hiroyuki;Fukui, Hiroyuki
过敏性鼻炎 (AR) 是一种炎症性疾病，典型症状包括打喷嚏、充血和鼻漏。组胺在引起 AR 症状中起着重要作用。在 AR 患者中观察到组胺 H-1 受体 (H1R) 和组氨酸脱羧酶 (HDC) mRNA 的上调。 Th2细胞因子也参与AR的发病机制。我们使用甲苯-2,4-二异氰酸酯 (TDI) 致敏大鼠和表达内源性 H1R 的 HeLa 细胞检查了甲磺司特对鼻部症状以及 H1R、HDC 和 IL-4 基因表达的影响。 TDI 刺激会增加 TDI 致敏大鼠的鼻部症状、HDC 活性、鼻腔灌洗液中的组胺含量以及 H1R、HDC 和 IL-4 mRNA 的表达。使用 suplatast 预处理 2 周可显着抑制 TDI 诱导的鼻部症状以及 H1R、HDC 和 IL-4 mRNA 的升高。 Suplatast 还抑制鼻粘膜中的 HDC 活性和鼻腔灌洗液中的组胺含量。正常大鼠鼻腔双侧注射IL-4上调H1R mRNA，而鼻内应用组胺则上调IL-4 mRNA。 Suplatast 抑制 HeLa 细胞中 IL-4 诱导的 H1R mRNA 上调。然而，它并不能抑制组胺诱导的 H1R mRNA 升高。这些结果表明，suplatast 通过分别抑制 HDC 和 IL-4 基因转录来抑制组胺和 IL-4 诱导的 H1R 基因表达，从而抑制 TDI 致敏大鼠的组胺信号传导，从而减轻鼻部症状。免疫学杂志，2009，183：2133-2141。
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-diisocyan ate (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 Journal of Immunology, 2009, 183: 2133-2141.