Barcena Maria Luisa, Breiter Anne, Temp Julia, Ladilov Yury, Regitz-Zagrosek Vera
Department of Urology, Eberhard Karls University of Tuebingen, 72074 Tuebingen, Germany.
Berlin Institute of Health, Institute for Gender in Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
Int J Mol Sci. 2025 Sep 5;26(17):8670. doi: 10.3390/ijms26178670.
Cardiovascular diseases are the leading cause of human death worldwide. The role of the female hormone estrogen (E2) in this context is subject of debate. E2 might counteract inflammation by acting on macrophages; however, the underlying cellular mechanisms remain poorly understood. In the current study, we used primary human macrophages to investigate the effects of E2 on the NAD-dependent deacetylase Sirt1, protein acetylation, and pro-inflammatory phenotype. Male and female primary monocytes from healthy adult individuals were polarized into pro-inflammatory M1 macrophages via treatment with LPS and IFN-γ followed by treatment with E2 for 24 h. While E2 treatment had no effect on the Sirt1 protein expression, it significantly increased the acetylation state of nuclear proteins p53 and Ku70. In addition, E2 increased NFκB-p65 expression exclusively in male M1 macrophages, while TNF-α was reduced in female M1 macrophages following E2 treatment. In male monocyte-like cells, E2 significantly reduced nuclear Sirt1 expression and increased Ku70 acetylation. The current study demonstrated that E2 treatment of human M1 macrophages leads to downregulation of nuclear Sirt1 and hyperacetylation of corresponding nuclear proteins. These molecular changes are associated with an enhancement of the pro-inflammatory phenotype in male primary macrophages, while an attenuation of inflammation was observed in female cells.
心血管疾病是全球人类死亡的主要原因。在这种情况下，女性激素雌激素（E2）的作用存在争议。E2可能通过作用于巨噬细胞来对抗炎症；然而，其潜在的细胞机制仍知之甚少。在本研究中，我们使用原代人巨噬细胞来研究E2对NAD依赖性脱乙酰酶Sirt1、蛋白质乙酰化和促炎表型的影响。来自健康成年个体的男性和女性原代单核细胞通过用脂多糖（LPS）和干扰素-γ（IFN-γ）处理极化成为促炎性M1巨噬细胞，随后用E2处理24小时。虽然E2处理对Sirt1蛋白表达没有影响，但它显著增加了核蛋白p53和Ku70的乙酰化状态。此外，E2仅在雄性M1巨噬细胞中增加NFκB-p65表达，而在E2处理后的雌性M1巨噬细胞中肿瘤坏死因子-α（TNF-α）减少。在雄性单核细胞样细胞中，E2显著降低核Sirt1表达并增加Ku70乙酰化。本研究表明，用E2处理人M1巨噬细胞会导致核Sirt1下调和相应核蛋白的过度乙酰化。这些分子变化与雄性原代巨噬细胞促炎表型的增强有关，而在雌性细胞中观察到炎症减弱。
