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Periovulatory and Interleukin (IL)-1—Dependent Reglation of IL-6 in the Immature Rat Ovary: A Specific IL-1 Receptor-Mediated Eicosanoid-Dependent Effect

Motomu Ando, MD

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore, Maryland; Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah

Eli Y. Adashi, MD

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore, Maryland; Division of Reproeuctive Sciences, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah; eadashi{at}hsc.utah.edu

Interleukin (IL)-6, traditionally an IL-1—induced immune regulator, is nevertheless synthesized by a variety of tissues including the ovary. The purposes of this communication were to assess the ovarian expression of IL-6, examine its cyclic variation, and study its regulation by IL-1, a putative intermediary in the ovulatory process. Molecular probing revealed IL-6 transcripts to be most abundant in the thymus, liver, and ovary, which suggests that, in relative terms, untreated immature whole ovarian tissue is a significant site of IL-6 gene expression. Treatment of immature rats with pregnant mare serum gonadotropins resulted in a meausrable, statistically significant (P < .05) increase in ovarian IL-6 mRNA compared with untreated controls. Isolated and indeed transient increments in the relative abundance of IL-6 transcripts were noted 4 hours after exposure to hCG, a point in time 8 hours from projected follicular rupture, a pattern highly reminiscent of that previously recognized for IL-1ß transcripts. Treatment of whole ovarian dispersates from immature rats with IL-1ß for 48 hours resulted in a significant (P < .05) increase (11-fold) over control in IL-6 transcripts. The IL-1 effect proved dose dependent; the first significant increase was noted at the 1-ng/mL dose level. Evaluation of the time requirements revealed IL-1ß to significantly (P < .05) up-reglate (4.5-fold) IL-6 transcripts as early as 24 hours into the culture period. Cotreatment with the IL-1 receptor antagonist completely reversed the IL-1 effect, which suggests mediation through a specific IL-1 receptor. Treatment with indomethacin (10 µg/mL), an established inhibitor of prostaglandin biosynthesis, resulted in a significant (P < .05) decrease (79%) in the ability of IL-1ß to up-regulate IL-6 transcripts. Importantly, the addition of prostaglandin E₂ (10 µg/mL) to untreated or indomethacin-treated cells significantly (P < .05) augmented the IL-1ß effect. This suggests a role for eicosanoid signaling in IL-1ß action. Treatment with aminoguanidine, an established inhibitor of nitric oxide synthase, significantly (P < .05) decreased (85%) the IL-1ß effect. However, the addition of S-nitroso-n-acetyl-penicilamine, an established nitrite generator, failed to reverse the aminoguanidine effect, which suggests that the inhibitor effect of aminoguanidine may be nitrite independent. Treatment with cycloheximide produced dose-dependent inhibition of the ability of IL-1 to up-regulate IL-6 transcripts; the maximal inhibitory effect was 89%. Taken together, these findings (1) reaffirm the rat ovary as a site of IL-6 expression; (2) document an in vivo increase in IL-6 transcripts before ovulation; (3) disclose a marked dependence of IL-6 on IL-1ß; and (4) reveal the IL-1ß effect to be dose and time dependent, receptor mediated, contingent upon de novo protein biosynthesis, and eicosanoid dependent but nitric oxide independent. These findings suggest that IL-1 action in the ovary may require the intemediacy of IL-6 in a manner like that encountered in extraovarian sites.

Key Words: Interleukin-1 • interleukin-6 • ovary

Journal of the Society for Gynecologic Investigation, Vol. 7, No. 5, 301-308 (2000)
DOI: 10.1177/107155760000700506


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