Rheumatology Section, Department of Medicine, Temple Autoimmunity Center, Temple University School of Medicine, Philadelphia, PA, USA.
Cell Death Dis. 2013 Aug 8;4(8):e758. doi: 10.1038/cddis.2013.251.
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.
细胞死亡可分为促炎的细胞凋亡和促炎的细胞坏死过程。坏死与凋亡一样，是一种受调控的细胞死亡形式，多聚（ADP-核糖）聚合酶-1（PARP-1）和受体相互作用蛋白（RIP）1/3 是主要的介质。我们之前的研究表明，PARP-1 的缺失或抑制可保护小鼠免受肾炎的侵害，但仅限于雄性小鼠。因此，我们假设在性别之间存在细胞死亡程序的固有差异。我们在此表明，在免疫介导的肾炎模型中，与雄性小鼠相比，雌性小鼠的凋亡增加。用雌激素处理雄性小鼠可诱导凋亡，使其水平与雌性小鼠相似，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了坏死。我们还表明 RIP-3 的缺失没有性别偏向。我们在此证明，雄性和雌性小鼠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 是性别偏向细胞死亡的两种介质。因此，我们建议根据性别靶向细胞死亡将导致为每个性别量身定制的更好的治疗方法。
