Oncostatin M is a potent inducer of hepcidin, the iron regulatory hormone
Oncostatin M is a potent inducer of hepcidin, the iron regulatory hormone
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DOI：
10.1096/fj.09-152561
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发表时间：
2010-06-01
期刊：
影响因子：
4.8
通讯作者：
Vaulont, Sophie
中科院分区：
文献类型：
--
作者：
Chung, Bomee;Verdier, Frederique;Vaulont, Sophie
已知红细胞生成活性通过调节肝脏铁调节激素铁调素影响铁稳态。为了鉴定由成红细胞分泌的可能影响铁调素合成的新因子，我们建立了共培养模型。与原代人成红细胞或红白血病UT 7细胞共培养的HuH 7肝癌细胞呈现铁调素基因表达的20至35倍增加。这种诱导在中和制瘤素M抗体存在下完全钝化，表明这种属于IL-6细胞因子家族的细胞因子负责增加铁调素表达水平。我们进一步证明了重组制瘤素M通过特异性激活STAT途径诱导HuH 7细胞中铁调素的显著转录增加。在原代培养的肝细胞中也观察到抑瘤素M对铁调素的诱导作用，并且认为铁调素具有细胞特异性，因为在分离的骨髓细胞、巨噬细胞、基质细胞和淋巴瘤衍生细胞系中均未发现诱导作用，在成红细胞中也未发现诱导作用。最后，我们表明，抑瘤素M管理在体内增加铁调素的表达，并导致显着降低血清铁水平。这项工作确定了肝脏中hepcidin表达的新的有效诱导剂，并支持制瘤素M信号通路调节剂在治疗铁紊乱中的作用。Chung，B.，Verdier，F.，Matak，P.，Deschemin，J. C.的方法，Mayeux，P.，Vaulont，S.抑瘤素M是铁调素（铁调节激素）的有效诱导剂。FASEB J.24，2093-2103（2010）。www.fasebj.org
Erythropoietic activity is known to affect iron homeostasis through regulation of the liver iron regulatory hormone hepcidin. To identify new factors secreted by the erythroblasts that could influence hepcidin synthesis, we set up a coculture model. HuH7 hepatoma cells cocultured with primary human erythroblasts or erythroleukemic UT7 cells presented a 20-to 35-fold increase of hepcidin gene expression. This induction was fully blunted in the presence of a neutralizing oncostatin M antibody, demonstrating that this cytokine, belonging to the IL-6 family of cytokines, was responsible for increased levels of hepcidin expression. We further demonstrated that recombinant oncostatin M induced a dramatic transcriptional increase of hepcidin in HuH7 cells through specific activation of the STAT pathway. Hepcidin induction by oncostatin M was also observed in hepatocytes in primary culture and is believed to be cell specific since no induction was found in isolated bone marrow cells, macrophagic, stromal, and lymphoma-derived cell lines, nor in erythroblasts. Finally, we show that oncostatin M administration in vivo increases hepcidin expression and leads to significantly decreased serum iron levels. This work identifies a new potent inducer of hepcidin expression in the liver and supports a role for modulators of oncostatin M signaling pathway in treating iron disorders.-Chung, B., Verdier, F., Matak, P., Deschemin, J.-C., Mayeux, P., Vaulont, S. Oncostatin M is a potent inducer of hepcidin, the iron regulatory hormone. FASEB J. 24, 2093-2103 (2010). www.fasebj.org