Department of Molecular Pharmacology, Division of Pharmaceutical Sciences, Institute of Health and Biosciences, The University of Tokushima, Tokushima, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2010 Apr;381(4):305-13. doi: 10.1007/s00210-010-0491-z. Epub 2010 Jan 30.
Histamine plays an important role in allergy mainly through histamine H1 receptor (H1R). Recent studies showed that the H1R level is elevated in allergic conditions, suggesting that this will make the allergic symptoms worse by intensifying H1R-mediated processes. Some cytokines are also involved in allergy, and interleukin-4 (IL-4) has been implicated as an important mediator of allergic inflammation. It is noteworthy that the level of IL-4 is elevated under allergic states. We tested whether IL-4 has a role in up-regulating H1R level by using the cultured human HeLa cell as a model system that expresses both IL-4 receptor and H1R. IL-4 stimulation increased H1R protein levels and H1R mRNA levels. IL-4 also increased H1R promoter activity, but had no effect on H1R mRNA stability, indicating that up-regulation of H1R was due to an increase in H1R mRNA synthesis. IL-4 activated STAT6 (signal transducer and activator of transcription 6) in HeLa cells, and up-regulation of H1R mRNA and activation of STAT6 by IL-4 were inhibited by a specific JAK3 (Janus-activated kinase 3) inhibitor. Stimulation with histamine also up-regulated H1R mRNA, and co-stimulation with histamine and IL-4 elevated H1R mRNA level significantly higher than the stimulation with histamine or IL-4 alone did. These results indicated that IL-4 up-regulated H1R mRNA level through increased transcription of H1R gene via JAK3-STAT6 pathway. The effects of histamine and IL-4 were additive, suggesting that these allergic mediators will work together to up-regulate H1R level, and thus make the allergic symptom worse by intensifying H1R-mediated allergic processes.
组胺通过组胺 H1 受体（H1R）在过敏中发挥重要作用。最近的研究表明，过敏状态下 H1R 水平升高，这表明通过增强 H1R 介导的过程，这将使过敏症状恶化。一些细胞因子也与过敏有关，白细胞介素-4（IL-4）已被认为是过敏炎症的重要介质。值得注意的是，过敏状态下 IL-4 水平升高。我们使用培养的人 HeLa 细胞作为表达 IL-4 受体和 H1R 的模型系统，测试了 IL-4 是否通过上调 H1R 水平发挥作用。IL-4 刺激增加了 H1R 蛋白水平和 H1R mRNA 水平。IL-4 还增加了 H1R 启动子活性，但对 H1R mRNA 稳定性没有影响，表明 H1R 的上调是由于 H1R mRNA 合成的增加。IL-4 在 HeLa 细胞中激活 STAT6（信号转导和转录激活因子 6），并且 IL-4 对 H1R mRNA 的上调和 STAT6 的激活被特异性 JAK3（Janus 激活激酶 3）抑制剂抑制。组胺刺激也上调了 H1R mRNA，组胺和 IL-4 的共同刺激使 H1R mRNA 水平显著高于单独用组胺或 IL-4 刺激时的水平。这些结果表明，IL-4 通过 JAK3-STAT6 途径增加 H1R 基因的转录来上调 H1R mRNA 水平。组胺和 IL-4 的作用是相加的，这表明这些过敏介质将共同作用以上调 H1R 水平，从而通过增强 H1R 介导的过敏过程使过敏症状恶化。
