Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, United Arab Emirates.
Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates.
Immunobiology. 2020 Sep;225(5):151995. doi: 10.1016/j.imbio.2020.151995. Epub 2020 Aug 2.
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 ERα 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-1α 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.
单核细胞释放或隔离铁的能力影响其在癌症和炎症中的作用。先前的研究表明，虽然白细胞介素 6 (IL-6) 上调铁调素合成并增强铁隔离，但 E2 减少铁调素合成并增加铁释放。鉴于 E2 上调单核细胞中 IL-6 的产生，E2 对单核细胞中铁代谢的确切影响很可能与其对 IL-6 表达的影响有关。为了解决这个问题，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。还评估了用 ERα 激动剂 PPT、ER 拮抗剂 ICI-182780、地塞米松+E2、IL-6+E2 以及 IL-6 沉默的 U937 细胞处理的 U937 细胞中的铁状态。E2 处理降低了 HuT-78、THP-1 和 Hep-G2 细胞中的铁调素合成，但增加了 U937 细胞中的铁调素合成并降低了 FPN 表达。E2 处理的 U937 细胞还显示出降低的 HIF-1α 和 FTH 表达以及增加的 TFR1 表达，与类似处理的 Hep-G2 细胞相比，这与不稳定铁含量增加相关。虽然白细胞介素 6 (IL-6) 处理 U937 细胞导致铁调素表达增加，但地塞米松处理导致铁调素合成减少，与 E2 或地塞米松+E2 处理的细胞相比；IL-6 沉默也导致 U937 细胞中铁调素合成减少。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和凋亡减少。这些发现表明，E2 以 IL-6 依赖的方式差异地改变单核细胞中的铁代谢。
