Differential regulation of pro-inflammatory necrosis in males and females by Poly (ADP-Ribose) Polymerase-1 and 17β estradiol (P5074)

Abstract

Abstract Cell death can be divided into the anti-inflammatory apoptosis and the pro-inflammatory 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 are two of the mediators. We previously showed that absence or inhibition of PARP-1 protects mice from immune mediated nephritis. Surprisingly, this protection showed a sex-bias, with only male mice being protected. Several studies have shown that the response of males and females to stress differs, although the basis for this sexual dimorphism remains to be determined. We hypothesized that these differences may be due to an inherent difference in the cell death program between the two sexes. We show here that in an immune mediated nephritis model, females show increased apoptosis compared to males. Treatment of males with estrogens inhibited necrosis but induced apoptosis to levels similar to those observed in females. Although PARP-1 was activated in both males and females, absence or inhibition of PARP-1 reduced necrosis only in males. Inhibition of RIP1 with Necrostatin-1 did not show sex bias. We demonstrate here that males and females are prone to different types of cell death. Our data also suggest that estrogens and PARP-1 are two of the mediators of sex-bias in cell death. We therefore propose that clinical targeting of cell death should differ based on sex and could lead to better treatments for each gender.