Mifepristone/RU486 acts in Drosophila melanogaster females to counteract the life span-shortening and pro-inflammatory effects of male Sex Peptide.

Males with null mutation of Sex Peptide (SP) gene were compared to wild-type males for the ability to cause physiological changes in females that could be reversed by mifepristone. Males from wild-type strains decreased median female life span by average -51%. Feeding mifepristone increased life span of these females by average +106%. In contrast, SP-null males did not decrease female life span, and mifepristone increased median life span of these females by average +14%, which was equivalent to the effect of mifepristone in virgin females (average +16%). Expression of innate immune response transgenic reporter (Drosocin-GFP) was increased in females mated to wild-type males, and this expression was reduced by mifepristone. In contrast, SP-null males did not increase Drosocin-GFP reporter expression in the female. Similarly, mating increased endogenous microbial load, and this effect was reduced or absent in females fed mifepristone and in females mated to SP-null males; no loss of intestinal barrier integrity was detected using dye-leakage assay. Reduction of microbial load by treating adult flies with doxycycline reduced the effects of both mating and mifepristone on life span. Finally, mifepristone blocked the negative effect on life span caused by transgenic expression of SP in virgin females. The data support the conclusion that the majority of the life span-shortening, immune-suppressive and pro-inflammatory effects of mating are due to male SP, and demonstrate that mifepristone acts in females to counteract these effects of male SP.