Iron overload inhibits BMP/SMAD and IL-6/STAT3 signaling to hepcidin in cultured hepatocytes.
Iron overload inhibits BMP/SMAD and IL-6/STAT3 signaling to hepcidin in cultured hepatocytes.
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DOI：
10.1371/journal.pone.0253475
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Pantopoulos K
中科院分区：
文献类型：
--
作者：
Charlebois E;Pantopoulos K
海普西丁是一种多肽荷尔蒙，它针对铁出口商铁蛋白，从而限制铁进入血液。它主要是在肝细胞中产生的，主要是对体内铁储存的增加或炎症迹象的反应。铁刺激肝窦内皮细胞骨形态发生蛋白6(Bmp6)的表达，Bmp6又与肝细胞上的BMP受体结合，诱导SMAD信号级联反应，转录激活编码海普西丁的HAMP mRNA。Smad信号也是IL-6/STAT3途径诱导炎性HAMP基因表达的重要途径。在这里，我们利用人Huh7肝癌细胞和原代小鼠肝细胞来评估铁干扰对海普西丁信号转导的影响。铁络合似乎稍微削弱了对海普西丁的信号传递。随后的补铁不仅不能逆转这些效应，而且显著降低基础HAMP mRNA，并抑制Bmp6和/或IL-6对HAMP mRNA的诱导。因此，过量的铁处理细胞以剂量依赖的方式抑制基础和Bmp6介导的Smad5磷酸化和HAMP、ID1和Smad7mRNAs的诱导。铁还抑制IL-6介导的STAT3磷酸化和HAMP和SOCS3mRNAs的诱导。伴随着这些反应的是GCLC和Hmox1mRNAs的诱导，这是氧化应激的已知标志。我们的结论是，肝细胞铁超载通过抑制各自配体下游的SMAD和STAT3信号通路来抑制海普西丁。
Hepcidin is a peptide hormone that targets the iron exporter ferroportin, thereby limiting iron entry into the bloodstream. It is generated in hepatocytes mainly in response to increased body iron stores or inflammatory cues. Iron stimulates expression of bone morphogenetic protein 6 (BMP6) from liver sinusoidal endothelial cells, which in turn binds to BMP receptors on hepatocytes and induces the SMAD signaling cascade for transcriptional activation of the hepcidin-encoding HAMP mRNA. SMAD signaling is also essential for inflammatory HAMP mRNA induction by the IL-6/STAT3 pathway. Herein, we utilized human Huh7 hepatoma cells and primary murine hepatocytes to assess the effects of iron perturbations on signaling to hepcidin. Iron chelation appeared to slightly impair signaling to hepcidin. Subsequent iron supplementation not only failed to reverse these effects, but drastically reduced basal HAMP mRNA and inhibited HAMP mRNA induction by BMP6 and/or IL-6. Thus, treatment of cells with excess iron inhibited basal and BMP6-mediated SMAD5 phosphorylation and induction of HAMP, ID1 and SMAD7 mRNAs in a dose-dependent manner. Iron also inhibited IL-6-mediated STAT3 phosphorylation and induction of HAMP and SOCS3 mRNAs. These responses were accompanied by induction of GCLC and HMOX1 mRNAs, known markers of oxidative stress. We conclude that hepatocellular iron overload suppresses hepcidin by inhibiting the SMAD and STAT3 signaling pathways downstream of their respective ligands.
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影响因子：
20.3
作者：
Falzacappa, Maria Vittoria Verga;Spasic, Maja Vujic;Muckenthaler, Martina U.
通讯作者：
Muckenthaler, Martina U.
影响因子：
20.3
作者：
Glickstein, H;Ben El, R;Cabantchik, ZI
通讯作者：
Cabantchik, ZI
影响因子：
20.3
作者：
Canali, Susanna;Zumbrennen-Bullough, Kimberly B.;Babitt, Jodie L.
通讯作者：
Babitt, Jodie L.
影响因子：
25.7
作者：
Graham, RM;Morgan, EH;Baker, E
通讯作者：
Baker, E
DOI：
10.1016/s0304-4165(97)00120-7
发表时间：
1998-03-12
影响因子：
3
作者：
Baker, E;Baker, SM;Morgan, EH
通讯作者：
Morgan, EH