Interleukin-1 Receptor Antagonist Suppresses Human Chorionic Gonadotropin-Induced Ovulation in the Rat1

Abstract

Indirect evidence has implicated the interleukin-1 (IL-1) system in ovulation. Thus, the ability of IL-1β to induce ovulation in rat and rabbit perfused ovaries has been demonstrated. In the present study, the involvement of the IL-1 system in ovulation was directly tested in vivo, in the rat model. For this purpose, the natural inhibitor of the IL-1 system, interleukin- receptor antagonist (IL-lra), was administered locally by use of an intrabursal injection route. Twenty-six-day-old Sprague-Dawley rats received injections of eCG (10 IU), followed 56 h later by hCG (15 IU). IL-lra (75 ,μg/bursa) was administered locally into the periovarian sac, 6 h (n = 5), 2 h (n = 11), and 0 h (n = 5) before hCG administration. Control animals (n = 10) received injections of the same volume (50 μ1) of vehicle (PBS). IL-lra administered locally into the periovarian sac inhibited ovulation from the treated ovary, reaching 40% inhibition (p < 0.05) when injected 2 h prior to hCG, as compared to the untreated contralateral ovary (6 ± 1.4 ova vs. 10 ± 1.8 ova) and PBS-injected control ovaries (6 ± 1.4 ova vs. 8.2 ± 0.7). Injection of IL- Ira 6 h before or concomitantly with hCG did not affect the ovulation rate. Internucleosomal DNA fragmentation was evaluated by 3′ end-labeling and autoradiography for detecting apoptotic changes. No difference in DNA fragmentation was found between treated and untreated ovaries. Morphologically, the failure of the cumulus complexes containing meiotically mature oocytes to detach from mural granulosa and to undergo expansion in ovaries treated with IL-lra 2 h before hCG suggests that IL-1 is involved in preovulatory changes in the cumulus oophorus. Our results demonstrate a time-dependent inhibition of ovulation by IL-lra, suggesting an autocrine-paracrine role of the rat ovarian IL-1 system in ovulation, which is not related to demonstrable ovarian apoptotic changes.