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Interleukin-1 deficiency prolongs ovarian lifespan in mice

Significance statement

Female mammals are endowed with a finite number of oocytes at birth which gradually decreases during pre-pubertal development and adult life. The fate of most follicles is atretic degeneration, a process that culminates in near exhaustion of the oocyte reserve, approximately at the fifth decade of life in women, leading to menopause. In the last two decades, difficulty conceiving is on the rise, partly due to a current trend of postponing childbearing into advanced maternal age. A corresponding upward trend in the number of In Vitro Fertilization (IVF) treatments is observed. Nonetheless, whereas cycle rate sharply increases, pregnancy rate and live births are only moderately elevated, stressing out the unmet need. Of note, a considerable number of IVF patients respond poorly to controlled-ovarian-hyperstimulation (only few retrieved oocytes, reduced number of embryos available for transfer and poor pregnancy rate). Recent studies in women suggest that inflammatory conditions may adversely affect ovarian reserve and are related to poor IVF outcomes. We recently found that gene deletion of the potent pro-inflammatory cytokine Interleukin-1 α results in attenuated apoptotic signaling in the ovary which ultimately leads to a prolonged ovarian lifespan as manifested by a higher pregnancy rate and bigger litter size in advanced chronological age. Furthermore, a significantly higher number of oocytes are retrieved from Interleukin-1 α-KO compared to WT oviducts in response to ovarian stimulation, starting from 2.5 months of age onwards. These findings highlight Interleukin-1 α as an important regulator of ovarian senescence. We suggest the blockade of Interleukin-1 α as a novel therapeutic approach to attenuate follicle loss as well as improve the ovarian response to hormonal stimulation. This therapeutic approach may provide a great assistance which is required in the management of poor response IVF patients.

Figure Legend: Representative micrographs of 2.5 months old WT and Interleukin-1 α-KO ovarian sections. Interleukin-1 α-KO ovaries contain significantly higher number of growing follicles (red arrows) compared to WT ovaries.

Interleukin-1 deficiency prolongs ovarian lifespan in mice. Global Medical Discovery

 

 

 

 

 

 

 

 

Journal Reference

Uri-Belapolsky S1, Shaish A2, Eliyahu E3, Grossman H4, Levi M4, Chuderland D4, Ninio-Many L4, Hasky N4, Shashar D2, Almog T2, Kandel-Kfir M2, Harats D2,Shalgi R4, Kamari Y5Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12492-7.

Show Affiliations

1The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer 52621, Israel; Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; and.

2The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer 52621, Israel;

3Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sin, New York, NY 10029.

4Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; and.

5The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer 52621, Israel; [email protected]

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 Interleukin-1  in the age-related exhaustion of ovarian reserve using Interleukin-1 α and Interleukin-1 β-KO mice. Interleukin-1 α-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 Interleukin-1 α-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. Interleukin-1 β-KO mice displayed a comparable but more subtle prolongation of ovarian  lifespan compared with Interleukin-1 α-KO mice. The protein and mRNA of both Interleukin-1 α and Interleukin-1 β 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 Interleukin-1 β, Interleukin-6, and TNF-α in ovaries of Interleukin-1 α-KO micecompared with WT mice. Taken together, Interleukin-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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