Interleukin (IL)-1 Deficiency Prolongs Ovarian Lifespan in Mice: A Link between Inflammatory Genes and Age-Related Exhaustion of Ovarian Reserve

Shiri Uri ^1,2 Aviv Shaish ² Efrat Eliyahu ³ Hadas Grossman ¹ Mattan Levi ¹ Dana Chuderland ¹ Lihi Ninio-Many ¹ Noa Hasky ¹ David Shashar ² Tal Almog ² Michal Kandel-Kfir ² Dror Harats ² Yehuda Kamari ² Ruth Shalgi ¹

¹Cell and Developmental Biology, Tel-Aviv University
²The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer
³3Genetics and Genomic Sciences, School of Medicine, Mount Sinai

Introduction: Apoptosis is the central mechanism responsible for oocytes loss. Recent reports suggested that uncontrolled inflammation may adversely affect ovarian reserve. We tested the possible role of the pro-inflammatory cytokine interleukin (IL)-1 in the age-related exhaustion of ovarian reserve, using IL-1α-knock-out (KO) mice.

Aim: Characterize the reproductive phenotype of IL-1α-KO mice and understand the underlying mechanism responsible for IL-1α-KO mice extended ovarian lifespan.

Materials & Methods: WT and IL-1α-KO female mice were allowed to mate for one month with WT male mice of proven fertility. Pregnant mice were sacrificed close to delivery and the number of fetuses per female was recorded. Mice were primed with gonadotropins and the number of ovulated oocytes was counted. We performed morphometric analysis on ovarian serial and serum anti-mullerian hormone (AMH) was measured using enzyme-linked immunoassay (ELISA).

Results: Pregnancy rate and litter size at advanced age of IL-1α-KO mice were higher than those of WT mice. The number of secondary and antral follicles was significantly higher in the ovaries of 2.5 months old IL-1α-KO mice than in WT mice ovaries. Serum AMH was markedly higher in IL-1α-KO mice at the ages of 2.5 months onward, along with a greater ovarian response to gonadotropins. IL-1α protein and mRNA were localized within developing follicles (oocytes and granulosa cells) and the ovarian IL-1α mRNA level increased with age. Molecular analysis showed a decreased apoptotic signaling in ovaries of IL-1α-KO mice, along with an increased expression of follicle-stimulating hormone receptor in primary granulosa cells of IL-1α-KO mice. Furthermore, a marked attenuation in the expression of genes coding for the pro-inflammatory cytokines IL-1β, IL-6 and TNFα was observed in ovaries of IL-1α-KO mice.

Conclusions: IL-1 emerges as an important participant in the age-related exhaustion of ovarian reserve, possibly by enhancing the expression of inflammatory genes and promoting apoptotic pathways.