Estrogen signaling differentially alters iron metabolism in monocytes in an Interleukin 6-dependent manner
Estrogen signaling differentially alters iron metabolism in monocytes in an Interleukin 6-dependent manner
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DOI：
10.1016/j.imbio.2020.151995
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发表时间：
2020-09-01
期刊：
影响因子：
2.8
通讯作者：
Hamad, Mawieh
中科院分区：
文献类型：
--
作者：
Bajbouj, Khuloud;Shafarin, Jasmin;Hamad, Mawieh
单核细胞释放或隔离铁的能力影响它们在癌症和炎症中的作用。以前的工作表明，虽然IL-6上调了海普西丁的合成并增强了铁的隔离，但雌二醇减少了海普西丁的合成并增加了铁的释放。鉴于E2上调单核细胞中IL-6的产生，它对单核细胞中铁代谢的确切影响很可能是通过其对IL-6表达的影响而形成的。为了解决这个问题，我们评估了E2处理的U937、HUT-78、THP-1和Hep-G2细胞中关键铁调节蛋白的表达。用ERA激动剂PPT、ER拮抗剂ICI-182780、地塞米松+/-E_2、IL-6+/-E_2处理的U937细胞和IL-6沉默的U937细胞的铁状态也被检测。雌二醇组HUT-78、THP-1和Hep-G2细胞的海普西丁合成减少，而U937细胞的海普西丁合成增加，FPN表达降低。与类似处理的Hep-G2细胞相比，E2处理的U937细胞HIF-1α和FTH表达降低，TFR1表达增加，这与活性铁含量增加有关。白介素6(IL-6)诱导的U937细胞中海普西丁的表达增加，地塞米松处理的U937细胞中海普西丁的合成较E_2或地塞米松+E_2处理的细胞减少，IL-6的沉默也导致U937细胞中海普西丁的合成减少。最后，虽然铁耗竭导致U937细胞死亡增加，但E2处理导致细胞存活增加，细胞凋亡率减少。这些发现表明，E2以IL-6依赖的方式不同地改变单核细胞的铁代谢。
The ability of monocytes to release or sequester iron affects their role in cancer and inflammation. Previous work has shown that while IL-6 upregulates hepcidin synthesis and enhances iron sequestration, E2 reduces hepcidin synthesis and increases iron release. Given that E2 upregulates IL-6 production in monocytes, it is likely that the exact effect of E2 on iron metabolism in monocytes is shaped by its effect on IL-6 expression. To address this issue, the expression of key iron regulatory proteins was assessed in E2-treated U937, HuT-78, THP-1 and Hep-G2 cells. Iron status was also evaluated in U937 cells treated with the ERa agonist PPT, the ER antagonist ICI-182780, dexamethasone +/- E2, IL-6 +/- E2 and in IL-6-silenced U937 cells. E2 treatment reduced hepcidin synthesis in HuT-78, THP-1 and Hep-G2 cells but increased hepcidin synthesis and reduced FPN expression in U937 cells. E2-treated U937 cells also showed reduced HIF-1 alpha and FTH expression and increased TFR1 expression, which associated with increased labile iron content as compared with similarly treated Hep-G2 cells. While treatment of U937 cells with interleukin 6 (IL-6) resulted in increased expression of hepcidin, dexamethasone treatment resulted in reduced hepcidin synthesis relative to E2- or dexamethasone + E2-treated cells; IL-6 silencing also resulted in reduced hepcidin synthesis in U937 cells. Lastly, while iron depletion resulted in increased cell death in U937 cells, E2 treatment resulted in enhanced cell survival and reduced apoptosis. These findings suggest that E2 differentially alters iron metabolism in monocytes in an IL-6 dependent manner.