Uchida Ryota, Xiang Huihui, Arai Hiroya, Kitamura Hidemitsu, Nishida Keigo
Laboratory of Immune Regulation, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science.
Division of Functional Immunology, Institute for Genetic Medicine, Hokkaido University.
Biol Pharm Bull. 2019 Jan 1;42(1):87-93. doi: 10.1248/bpb.b18-00565. Epub 2018 Nov 10.
The trace element zinc is essential for the immune system, and its dysregulation and deficiency results in impaired immune function. Recent studies have shown that zinc can behave as an intracellular signaling molecule in immune cells. We have previously demonstrated that L-type calcium channel (LTCC) is involved in the regulation of zinc signaling, Zinc wave and cytokine production by stimulating Fc epsilon receptor for immunoglobulin E (IgE) in mast cells. However, it is not known whether LTCC-mediated Zinc wave is required for cytokine production by stimulation of toll-like receptors and cytokine receptors in mast cells. Here we report that stimulation of toll-like receptors and cytokine receptors can induce Zinc wave in mast cells and regulate the expression of cytokine genes. The LTCC antagonist nicardipine inhibited lipopolysaccharide (LPS)- and interleukin-33 (IL-33)-mediated Zinc wave and the induction of cytokine genes such as IL-6. Consistent with these results, the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) also inhibited LPS- and IL-33-induced cytokine gene expression. Furthermore, LPS induced Zinc wave not only in mast cells but also in dendritic cells. Together, these observations show that Zinc wave is activated by various stimuli and is linked to cytokine gene induction in immune cells.
微量元素锌对免疫系统至关重要，其失调和缺乏会导致免疫功能受损。最近的研究表明，锌在免疫细胞中可作为一种细胞内信号分子。我们之前已经证明，L型钙通道（LTCC）通过刺激肥大细胞中免疫球蛋白E（IgE）的Fcε受体参与锌信号传导、锌波和细胞因子产生的调节。然而，尚不清楚LTCC介导的锌波是否是肥大细胞中通过刺激Toll样受体和细胞因子受体产生细胞因子所必需的。在此我们报告，刺激Toll样受体和细胞因子受体可在肥大细胞中诱导锌波并调节细胞因子基因的表达。LTCC拮抗剂尼卡地平抑制脂多糖（LPS）和白细胞介素-33（IL-33）介导的锌波以及IL-6等细胞因子基因的诱导。与这些结果一致，锌螯合剂N,N,N',N'-四（2-吡啶甲基）乙二胺（TPEN）也抑制LPS和IL-33诱导的细胞因子基因表达。此外，LPS不仅在肥大细胞中诱导锌波，在树突状细胞中也能诱导。总之，这些观察结果表明，锌波可被多种刺激激活，并与免疫细胞中细胞因子基因的诱导相关。
