Ravasi Giulia, Pelucchi Sara, Greni Federico, Mariani Raffaella, Giuliano Andrea, Parati Gianfranco, Silvestri Laura, Piperno Alberto
Department of Health Science, University Milano-Bicocca, Monza, Italy.
San Gerardo Hospital, Monza, Italy.
Blood Cells Mol Dis. 2014 Dec;53(4):204-10. doi: 10.1016/j.bcmd.2014.06.006. Epub 2014 Jul 22.
Hepcidin transcription is strongly down-regulated under hypoxic conditions, however whether hypoxia inhibits hepcidin directly or indirectly is still unknown. We investigated the time course of hypoxia-mediated hepcidin down-regulation in vivo in healthy volunteers exposed to hypobaric hypoxia at high altitude and, based on the hypothesis that circulating factors are implicated in hepcidin inhibition, we analyzed the effect of sera of these volunteers exposed to normoxia and hypoxia on hepcidin expression in Huh-7 cell lines. Hypoxia led to a significant hepcidin down-regulation in vivo that was almost complete within 72h of exposure and followed erythropoietin induction. This delay in hepcidin down-regulation suggests the existence of soluble factor/s regulating hepcidin production. We then stimulated HuH-7 cells with normoxic and hypoxic sera to analyze the effects of sera on hepcidin regulation. Hypoxic sera had a significant inhibitory effect on hepcidin promoter activity assessed by a luciferase assay, although the amount of such decrease was not as relevant as that observed in vivo. Cellular mRNA analysis showed that a number of volunteers' sera inhibited hepcidin expression, concurrently with ID1 inhibition, suggesting that inhibitory factor(s) may act through the SMAD-pathway.
在低氧条件下，铁调素转录被强烈下调，然而低氧是直接还是间接抑制铁调素仍不清楚。我们研究了在高海拔低氧环境下健康志愿者体内低氧介导的铁调素下调的时间进程，并且基于循环因子参与铁调素抑制的假设，我们分析了这些暴露于常氧和低氧环境下的志愿者的血清对Huh-7细胞系中铁调素表达的影响。低氧导致体内铁调素显著下调，在暴露72小时内几乎完全下调，并伴随促红细胞生成素的诱导。铁调素下调的这种延迟表明存在调节铁调素产生的可溶性因子。然后我们用常氧和低氧血清刺激HuH-7细胞，以分析血清对铁调素调节的影响。通过荧光素酶测定评估，低氧血清对铁调素启动子活性有显著抑制作用，尽管这种降低的程度不如在体内观察到的那样明显。细胞mRNA分析表明，许多志愿者的血清抑制铁调素表达，同时抑制ID1，这表明抑制因子可能通过SMAD途径发挥作用。
