CYTOKINE-MEDIATED REGULATION OF RAT OVARIAN-FUNCTION - INTERLEUKIN-1 STIMULATES THE ACCUMULATION OF A 92-KILODALTON GELATINASE

It is now known that the mammalian ovary possesses a complete interleu kin-1 (IL-1) system replete with ligands, receptors, and a receptor an tagonist. To further assess the hypothesis that IL-1 may play an inter mediary role in gonadotropin-triggered ovulation, we have set out to d etermine whether IL-1 is capable of promoting ovarian collagenase bios ynthesis, an established component of the ovulatory cascade. Untreated cultured whole ovarian dispersates from immature (25 day old) rats co nstitutively elaborated several collagenolytic species as assessed in a gelatin matrix. A major 72 kilodalton (kDa) gelatinase (GL) was part icularly apparent. Treatment with IL-1beta produced selective dose- an d cell density-dependent increments in the accumulation of a 92-kDa GL species. Administration of an IL-1 receptor antagonist neutralized th e IL-1-induced stimulation of the 92-kDa GL in a dose-dependent fashio n thereby supporting the presumption that the IL-1 effect is receptor mediated. Studies of comparable cellular densities of granulosa or enr iched theca-interstitial cultures demonstrated the IL-1 induced 92-kDa GL to be highly expressed in the enriched theca-interstitial but not in the isolated granulosa cell preparations. Treatment with transformi ng growth factor-beta1, a putative regulator of IL-1 action, significa ntly attenuated IL-1-induced 92-kDa GL accumulation thereby suggesting a potential regulatory paracrine/autocrine role for this agent in ova rian gelatinase economy. Initial characterization revealed the 92-kDa GL species to be a metalloproteinase present in its proenzyme zymogeni c form. Taken together, our present findings reveal the ovarian expres sion of a constitutive 72-kDa GL and of an IL-1-stimulated 92-kDa GL t he accumulation of which is particularly marked in enriched theca-inte rstitial preparations. These observations, along with the demonstratio n of the gonadotropin-dependent preovulatory induction of ovarian IL-1 gene expression, provide strong indirect support for the view that IL -1 may be the centerpiece of an intraovarian regulatory loop concerned with the promotion of the ovulatory cascade.