Interleukin-1 deficiency prolongs ovarian lifespan in mice

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 withWT 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.

Original languageEnglish
Pages (from-to)12492-12497
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number34
DOIs
StatePublished - 26 Aug 2014

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