Regulating ferroportin‐1 and transferrin receptor‐1 expression: A novel function of hydrogen sulfide.

Hydrogen sulfide (H2S) 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 2S 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 2S 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 2S 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 2S 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 2S, 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 2S is a key player in iron homeostasis under not only the inflamed conditions but also uninflamed conditions. H2S 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. Under uninflamed conditions, the regulation of Fpn1 and TfR1 expression by H 2S, both in vivo and in vitro, are mediated by the 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 2S is a key player in iron homeostasis under not only the inflamed conditions but also uninflamed conditions. [ABSTRACT FROM AUTHOR]