Interleukin-1 deficiency prolongs ovarian lifespan in mice (Aug 2014)

Interleukin-1 deficiency prolongs ovarian lifespan in mice
Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12492-7
Shiri Uri-Belapolsky, Aviv Shaish, Efrat Eliyahu, Hadas Grossman, Mattan Levi, Dana Chuderland, Lihi Ninio-Many, Noa Hasky, David Shashar , Tal Almog, Michal Kandel-Kfir , Dror Harats, Ruth Shalgi, Yehuda Kamari


Short description:
Females are subjected to a biological clock that dictates the end of the reproductive lifespan, on average, at 50 y of age, whereas fecundity sharply decreases after 30 y of age. Over the past decade, a current trend of postponing childbearing into advanced age has led to a corresponding upward trend in the number of in vitro fertilization (IVF) treatments. Inflammation was reported to affect both IVF outcomes and the ovarian reserve adversely. Identifying a possible culprit, such as IL-1, may offer new insight into the mechanisms responsible for oocyte loss as well as practical interventions, such as IL-1 blockade, which aims to slow down the rate at which oocytes are eliminated and improve IVF outcomes.
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Abstract taken from PubMed

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-KOmice 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 ovarianreserve, 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 micewere 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 WTmice. 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.
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