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Effect of Interleukin-1 Receptor Antagonist Gene Deletion on Male Mouse Fertility

The Shraga Segal Department of Microbiology and Immunology (M.H., M.G., M.A., N.C., R.A.), Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; Department of Obstetrics and Gynecology (E.L., N.W.), Soroka University Medical Center, Beer-Sheva 84101, Israel; and The Mina and Everard Goodman Faculty of Life Sciences (S.B.-S.I., H.B.), Bar-Ilan University, Ramat-Gan 52900, Israel

Address all correspondence and requests for reprints to: Professor Mahmoud Huleihel, Ph.D., The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. E-mail: huleihel{at}bgu.ac.il.

Members of the IL-1 family are pleiotropic cytokines that are involved in inflammation, immunoregulation, and other homeostatic functions in the body. IL-1, IL-1β, and the IL-1 antagonistic molecule [IL-1 receptor antagonist (IL-1 Ra)] are present in the testis under normal homeostasis, and they further increase upon infection/inflammation. In the present study, we examined the effect of IL-1 Ra gene deletion on male mouse fertility. Male mice [wild type (WT) and IL-1 Ra knockout (KO)] were mated with WT females, and the birth and number of offspring were recorded 21–45 d after mating. Furthermore, the concentration, motility, and morphology of sperm isolated from the cauda of the epididymis were evaluated. The ability of the calcium ionophore (A23187) to induce acrosome reaction (AR) in the sperm of WT and IL-1 Ra KO mice was compared with their ability to fertilize in vitro oocytes from WT females. The direct effect of IL-1 and IL-1β on AR and abnormal morphology in sperm from WT were evaluated. The levels of IL-1 and IL-1β in the testes of WT and IL-1 Ra KO mice were examined by specific ELISA and real-time PCR. Our results show a significant reduction in the capacity of IL-1 Ra KO male mice to fertilize WT females (P < 0.05). Furthermore, the number of offspring in mice fertilized with IL-1 Ra KO male mice was significantly lower than with WT males (P < 0.05). Sperm concentration and the percentage of motile sperm from IL-1 Ra KO and WT were similar; however, the percentage of sperm with abnormal morphology (mainly in the head) and acrosome-reacted sperm cells were significantly higher in the IL-1 Ra KO, compared with that of WT males (P < 0.05). In vitro, the ability of sperm from IL-1 Ra KO male mice to fertilize oocytes from WT females was significantly lower than sperm from WT mice (P < 0.05). In addition, the percentage of reacted sperm from IL-1 Ra KO, spontaneously without ionophore induction, was significantly higher than from WT (P < 0.05). Sperm from WT underwent induction of AR only by ionophore; however, sperm from IL-1 Ra KO were unable to undergo the AR by ionophore, indicating that they are induced and, thus, are inactive in fertilization. Testicular IL-1 and IL-1β levels were significantly higher in IL-1 Ra KO, compared with WT male mice (P < 0.05). The addition of recombinant IL-1 or IL-1β to sperm from a WT mouse induced their AR, and significantly increased abnormal sperm morphology, as compared with controls (P < 0.05). This effect was neutralized by the addition of IL-1 Ra. Our results indicate the involvement of IL-1 in sperm physiology, affecting its morphology and fertilization ability. Higher than homeostatic levels of IL-1 in the testis, as observed in IL-1 Ra KO mice, impaired the ability of sperm to fertilize oocytes. Together, these results may explain some of the male infertility cases with an infection/inflammation background and may hint at the ability to use IL-1 Ra in future therapeutic strategies in these cases.