Interleukin-1 deficiency prolongs ovarian lifespan in mice

Abstract

Oocyte endowment dwindles away during prepubertal and adult life until menopause occurs, and apoptosis has been identified as a central mechanism responsible for oocyte elimination. A few recent reports suggest that uncontrolled inflammation may adversely affect ovarian reserve. We tested the possible role of the proinflammatory cytokine IL-1 in the age-related exhaustion of ovarian reserve using IL-1α and IL-1β-KO mice. IL-1α-KO mice showed a substantially higher pregnancy rate and litter size compared with WT mice at advanced age. The number of secondary and antral follicles was significantly higher in 2.5-mo-old IL-1α-KO ovaries compared with WT ovaries. Serum anti-Müllerian hormone, a putative marker of ovarian reserve, was markedly higher in IL-1α-KO mice from 2.5 mo onward, along with a greater ovarian response to gonadotropins. IL-1β-KO mice displayed a comparable but more subtle prolongation of ovarian lifespan compared with IL-1α-KO mice. The protein and mRNA of both IL-1α and IL-1β mice were localized within the developing follicles (oocytes and granulosa cells), and their ovarian mRNA levels increased with age. Molecular analysis revealed decreased apoptotic signaling [higher B-cell lymphoma 2 (BCL-2) and lower BCL-2-associated X protein levels], along with a marked attenuation in the expression of genes coding for the proinflammatory cytokines IL-1β, IL-6, and TNF-α in ovaries of IL-1α-KO mice compared with WT mice. Taken together, IL-1 emerges as an important participant in the age-related exhaustion of ovarian reserve in mice, possibly by enhancing the expression of inflammatory genes and promoting apoptotic pathways.

Interleukin 1-alpha deficiency increases the expression of Follicle-stimulating hormone receptors in granulosa cells

“…Our previous studies indicated that, throughout their reproductive lifespan, Il1a ‐knockout (KO) mice exhibit a significantly increased ovarian response to gonadotropins compared to wild‐type (WT) mice (Uri‐Belapolsky et al, ). We validated the cellular expression of Fshr in primary GCs from Il1a ‐KO mice, and found significantly higher Fshr transcript and FSHR protein abundance in ovaries of KO compared to WT mice (Figure ).…”

“…Among the cytokines, IL1 is known to influence many aspects of ovarian function, including ovulation (Brännström, ; Gérard et al, ; Simón, ); however, which local processes are affected is not clear. IL1A is enriched within the oocyte and GCs throughout follicular development (Uri‐Belapolsky et al, ). We demonstrated that, in contrast to IL1B modulation (Ono et al, ), ovarian Il1a mRNA levels are reduced following gonadotropin triggering of ovulation.…”

Reproductive age-associated fibrosis in the stroma of the mammalian ovary

“…Further defining the inflammatory milieu of the aging ovary and determining whether multinucleated macrophage giant cells are a cause or consequence of chronic inflammation are warranted and currently under investigation. Ultimately modulating pro-inflammatory pathways may be an important therapeutic avenue for prolonging reproductive lifespan because, for example, in a mouse knockout model of the pro-inflammatory cytokine IL-1α, the ovarian lifespan, pregnancy rate, and litter size were all increased relative to age-matched controls (Uri-Belapolsky, et al 2014). …”

Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice

“…However, controversy remains regarding whether the increased follicular atresia with aging is eliciting a pro-inflammatory response in the ovaries or if the increased overall pro-inflammatory status with aging is accelerating the depletion of the ovarian follicular reserve. Recently, it was demonstrated that IL-1 knockout mice have delayed ovarian aging (Uri-Belapolsky et al, 2014), suggesting an active role for the inflammatory response in the process of follicle depletion. We also observed that IL-1 production was one of the down-regulated biological processes in old df/df compared to old N mice.…”