Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin-4 genes.
Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin-4 genes.
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DOI：
10.1002/prp2.166
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发表时间：
2015-10
影响因子：
2.6
通讯作者：
Fukui H
中科院分区：
文献类型：
--
作者：
Mizuguchi H;Nariai Y;Kato S;Nakano T;Kanayama T;Kashiwada Y;Nemoto H;Kawazoe K;Takaishi Y;Kitamura Y;Takeda N;Fukui H
苦参素含有抗过敏化合物，可抑制组胺H1受体(H1R)和白细胞介素4(IL)-4基因表达上调。然而，其潜在的机制仍不清楚。我们试图鉴定一种苦参素衍生的抗过敏化合物，并研究其作用机制。用实时荧光定量RT-PCR检测H1R和IL-4mRNA水平。采用甲苯-2，4-二异氰酸酯(TDI)致敏大鼠作为鼻腔超敏动物模型，观察马钱子碱在体内的作用。我们确定(−)-maackiain为负责成分。人工合成的Maackiain对IL-4基因的表达具有立体选择性，但对H1R基因的表达不具有立体选择性，提示转录信号的靶蛋白是不同的。(−)-Maackiain抑制PKCδ向高尔基体的易位和PKCδ上311酪氨酸的磷酸化，从而抑制H1R基因的转录。然而，(−)-Maackiain本身没有表现出任何抗氧化活性或对PKCδ酶活性的抑制作用。马钱子因可减轻TDI致敏大鼠的鼻部症状，抑制TDI致敏大鼠H1R和IL-4基因表达的上调。这些数据表明，(−)-Maackiain是一种新型的抗过敏化合物，通过抑制H1R和IL-4基因的表达来减轻TDI致敏模型大鼠的鼻部症状。其抑制H1R基因表达的分子机制是通过抑制蛋白激酶Cδ的激活而实现的。
Kujin contains antiallergic compounds that inhibit upregulation of histamine H1 receptor (H1R) and interleukin (IL)-4 gene expression. However, the underlying mechanism remains unknown. We sought to identify a Kujin-derived antiallergic compound and investigate its mechanism of action. The H1R and IL-4 mRNA levels were determined by real-time quantitative RT-PCR. To investigate the effects of maackiain in vivo, toluene-2,4-diisocyanate (TDI)-sensitized rats were used as a nasal hypersensitivity animal model. We identified (−)-maackiain as the responsible component. Synthetic maackiain showed stereoselectivity for the suppression of IL-4 gene expression but not for H1R gene expression, suggesting distinct target proteins for transcriptional signaling. (−)-Maackiain inhibited of PKCδ translocation to the Golgi and phosphorylation of Tyr311 on PKCδ, which led to the suppression of H1R gene transcription. However, (−)-maackiain did not show any antioxidant activity or inhibition of PKCδ enzymatic activity per se. Pretreatment with maackiain alleviated nasal symptoms and suppressed TDI-induced upregulations of H1R and IL-4 gene expressions in TDI-sensitized rats. These data suggest that (−)-maackiain is a novel antiallergic compound that alleviates nasal symptoms in TDI-sensitized allergy model rats through the inhibition of H1R and IL-4 gene expression. The molecular mechanism underlying its suppressive effect for H1R gene expression is mediated by the inhibition of PKCδ activation.