Differential regulation of cell death programs in males and females by Poly (ADP-Ribose) Polymerase-1 and 17β estradiol.
Differential regulation of cell death programs in males and females by Poly (ADP-Ribose) Polymerase-1 and 17β estradiol.
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DOI：
10.1038/cddis.2013.251
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发表时间：
2013-08-08
影响因子：
9
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细胞死亡可分为凋亡的抗炎过程和坏死的促炎过程。坏死与凋亡一样，是细胞死亡的一种调节形式，多聚腺苷二磷酸核糖聚合酶-1（PARP-1）和受体相互作用蛋白（RIP）1/3是主要的介导物。我们先前表明，PARP-1的缺乏或抑制可保护小鼠免于肾炎，但仅限于雄性小鼠。因此，我们假设两性之间的细胞死亡程序存在固有差异。我们在这里表明，在免疫介导的肾炎模型中，雌性小鼠显示出增加的细胞凋亡相比，雄性小鼠。用雌激素处理雄性小鼠，诱导细胞凋亡至与雌性小鼠相似的水平，并抑制坏死。尽管PARP-1在雄性和雌性小鼠中均被激活，但PARP-1抑制仅在雄性小鼠中减少坏死。我们还表明，RIP-3的删除没有性别偏见。我们在这里证明，雄性和雌性小鼠容易发生不同类型的细胞死亡。我们的数据还表明，雌激素和PARP-1是细胞死亡中性别偏见的两个介质。因此，我们建议基于性别的细胞死亡靶向将导致为每个性别量身定制和更好的治疗。
Cell death can be divided into the anti-inflammatory process of apoptosis and the pro-inflammatory process of necrosis. Necrosis, as apoptosis, is a regulated form of cell death, and Poly-(ADP-Ribose) Polymerase-1 (PARP-1) and Receptor-Interacting Protein (RIP) 1/3 are major mediators. We previously showed that absence or inhibition of PARP-1 protects mice from nephritis, however only the male mice. We therefore hypothesized that there is an inherent difference in the cell death program between the sexes. We show here that in an immune-mediated nephritis model, female mice show increased apoptosis compared to male mice. Treatment of the male mice with estrogens induced apoptosis to levels similar to that in female mice and inhibited necrosis. Although PARP-1 was activated in both male and female mice, PARP-1 inhibition reduced necrosis only in the male mice. We also show that deletion of RIP-3 did not have a sex bias. We demonstrate here that male and female mice are prone to different types of cell death. Our data also suggest that estrogens and PARP-1 are two of the mediators of the sex-bias in cell death. We therefore propose that targeting cell death based on sex will lead to tailored and better treatments for each gender.