Laboratory of Neuropharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Laboratory of Neuropharmacology, Institute of Translational & Precision Medicine, Nantong University, Nantong, China.
J Cell Physiol. 2019 Apr;234(4):3158-3169. doi: 10.1002/jcp.27431. Epub 2018 Oct 28.
Hydrogen sulfide (H S) has a significant effect on the regulation of interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) activities, while IL-6 directly regulates hepcidin expression via STAT3. We therefore hypothesized that H S has a role in body iron homeostasis by regulating the expression of iron transport proteins via the IL-6/STAT3/Hepcidin pathway. Here, we investigated the effects of two H S donors sodium hydrosulfide and GYY4137 on the expression of ferroportin-1 (Fpn1), transferrin receptor-1 (TfR1), hepcidin, IL-6 and pSTAT3 in the spleen of mice in vivo and peritoneal macrophage in vitro. We also examined the effects of H S on serum iron, transferrin saturation, and ferritin light chain contents in the spleen, and on nitrite content, nuclear factor erythroid 2-related factor-2 (Nrf2) and iron regulatory protein 1 (IRP1) in the macrophages. We demonstrated that H S regulates the expression of TfR1 and Fpn1 in the spleen in vivo and in peritoneal macrophages in vitro predominantly via the IL-6/pSTAT3/hepcidin pathway, under the conditions of inflammation induced by lipopolysaccharides. We also provide evidence that under uninflamed conditions, the regulation of Fpn1 and TfR1 expression by H S, both in vivo and in vitro, are mediated by the nitric oxide (NO)/Nrf2 and iron regulatory protein/iron responsive element pathways, respectively, which are independent of IL-6/pSTAT3/hepcidin signals. These findings show that H S is a key player in iron homeostasis under not only the inflamed conditions but also uninflamed conditions.
硫化氢（H2S）对白细胞介素-6（IL-6）和信号转导子和转录激活子 3（STAT3）活性的调节有显著影响，而 IL-6 则通过 STAT3 直接调节铁调素的表达。因此，我们假设 H2S 通过调节铁转运蛋白的表达来参与机体铁稳态的调节，其机制可能与 IL-6/STAT3/铁调素通路有关。在这里，我们研究了两种 H2S 供体硫氢化钠和 GYY4137 对体内小鼠脾脏和体外腹腔巨噬细胞中铁蛋白-1（Fpn1）、转铁蛋白受体-1（TfR1）、铁调素、IL-6 和 pSTAT3 的表达的影响。我们还研究了 H2S 对脾脏中血清铁、转铁蛋白饱和度和铁蛋白轻链含量以及巨噬细胞中硝酸盐含量、核因子红细胞 2 相关因子-2（Nrf2）和铁调节蛋白 1（IRP1）的影响。结果表明，在脂多糖诱导的炎症条件下，H2S 通过 IL-6/pSTAT3/铁调素通路主要调节体内脾脏和体外腹腔巨噬细胞中 TfR1 和 Fpn1 的表达。此外，我们还提供了证据表明，在非炎症条件下，H2S 对体内和体外 Fpn1 和 TfR1 表达的调节分别通过一氧化氮（NO）/Nrf2 和铁调节蛋白/铁反应元件通路介导，这两条通路与 IL-6/pSTAT3/铁调素信号通路无关。这些发现表明，H2S 不仅在炎症条件下，而且在非炎症条件下也是铁稳态的关键调节因子。
