STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation
STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation
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DOI：
10.1182/blood-2006-07-033969
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发表时间：
2007-01-01
期刊：
影响因子：
20.3
通讯作者：
Muckenthaler, Martina U.
中科院分区：
文献类型：
--
作者：
Falzacappa, Maria Vittoria Verga;Spasic, Maja Vujic;Muckenthaler, Martina U.
铁调素是肝脏产生的一种关键铁调节激素。不适当的低铁调素水平导致铁过载，而增加的铁调素表达通过限制肠铁吸收和巨噬细胞铁释放在炎症性贫血（At）中起重要作用。其表达响应于身体铁储存、缺氧以及至少部分涉及由巨噬细胞分泌的细胞因子的炎症和感染刺激而被调节。在这项研究中，我们建立了IL 6介导的hepcidin在人肝细胞系Huh 7中的激活，并进行了表征。我们表明，铁调素启动子的近端165 bp是铁调素激活响应外源性给药的IL 6或条件培养基从单核细胞/巨噬细胞系THP-1的关键。重要的是，我们表明，铁调素激活这些刺激需要STAT 3结合基序位于位置-64/-72的启动子。在对照培养条件下，高基础水平的铁调素mRNA表达也需要相同的STAT结合位点，并且sIRNA介导的STAT 3 RNA敲低强烈降低了铁调素mRNA表达。这些结果确定了铁调素急性期激活中缺失的环节，并确立了STAT 3作为基线铁调素表达和炎症状态期间的关键效应子。(c)2007年美国血液学会
Hepcidin is a key iron-regulatory hormone produced by the liver. Inappropriately low hepcidin levels cause iron overload, while increased hepcidin expression plays an important role in the anemia of inflammation (At) by restricting intestinal iron absorption and macrophage iron release. Its expression is modulated in response to body iron stores, hypoxia, and inflammatory and infectious stimuli involving at least in part cytokines secreted by macrophages. In this study we established and characterized IL6-mediated hepcidin activation in the human liver cell line Huh7. We show that the proximal 165 bp of the hepcidin promoter is critical for hepcidin activation in response to exogenously administered IL6 or to conditioned medium from the monocyte/macrophage cell line THP-1. Importantly, we show that hepcidin activation by these stimuli requires a STAT3 binding motif located at position -64/-72 of the promoter. The same STAT binding site is also required for high basal-level hepcidin mRNA expression under control culture conditions, and sIRNA-mediated RNA knockdown of STAT3 strongly reduces hepcidin mRNA expression. These results identify a missing link in the acute-phase activation of hepcidin and establish STAT3 as a key effector of baseline hepcidin expression and during inflammatory conditions. (c) 2007 by The American Society of Hematology