Cytokine-mediated regulation of rat ovarian function: interleukin-1 stimulates the accumulation of a 92-kilodalton gelatinase

Abstract

It is known that the mammalian ovary possesses a complete interleukin-1 (IL-1) system replete with ligands, receptors, and a receptor antagonist. To further assess the hypothesis that IL-1 may play an intermediary role in gonadotropin-triggered ovulation, we have set out to determine whether IL-1 is capable of promoting ovarian collagenase biosynthesis, an established component of the ovulatory cascade. Untreated cultured whole ovarian dispersates from immature (25 day old) rats constitutively elaborated several collagenolytic species as assessed in a gelatin matrix. A major 72 kilodalton (kDa) gelatinase (GL) was particularly apparent. Treatment with IL-1 beta produced selective dose- and cell density-dependent increments in the accumulation of a 92-kDa GL species. Administration of an IL-1 receptor antagonist neutralized the IL-1-induced stimulation of the 92-kDa GL in a dose-dependent fashion thereby supporting the presumption that the IL-1 effect is receptor mediated. Studies of comparable cellular densities of granulosa or enriched 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 transforming growth factor-beta 1, a putative regulator of IL-1 action, significantly attenuated IL-1-induced 92-kDa GL accumulation thereby suggesting a potential regulatory paracrine/autocrine role for this agent in ovarian gelatinase economy. Initial characterization revealed the 92-kDa GL species to be a metalloproteinase present in its proenzyme zymogenic form. Taken together, our present findings reveal the ovarian expression of a constitutive 72-kDa GL and of an IL-1-stimulated 92-kDa GL the accumulation of which is particularly marked in enriched theca-interstitial preparations. These observations, along with the demonstration 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.

Changes in Interleukin-1 Production of Peritoneal Macrophages during Estrous Cycle in Golden Hamsters.

“…IL-1 also increased the productions of prostaglandins [11], hyaluronic acid and proteoglycan [14] and gelatinase [15], which may be related to changes associated with the ovulatory process. In fact, IL-1f3 stimulated ovulation in rabbits [23], and an anti-ovulatory effect of IL-1 receptor antagonist was demonstrated in rats [24,25], but the effect of IL-1 on ovarian functions is dependent on the stage of follicular development.…”

“…The macrophage in particular is one of the key factors in the immune system and has been reported to be present in the ovary [3,4] [15]. It is also reported that IL-1 activity in human macrophages is influenced by gonadal steroids [16].…”

The midcycle increase in ovarian glucose uptake is associated with enhanced expression of glucose transporter 3. Possible role for interleukin-1, a putative intermediary in the ovulatory process.

“…Third, some components of the intraovarian IL-1 system (e.g., IL-1 ␤ and the type I IL-1 receptor) appear to be expressed in vivo, mainly during a narrow periovulatory window (6)(7)(8)(9)(10)(11)(12). Fourth, IL-1 ␤ has been shown to induce a host of ovulation-associated phenomena in vitro, such as the promotion of prostaglandin production (13)(14)(15)(16), the stimulation of hyaluronic acid biosynthesis (17), the induction of collagenase activity (18), and the activation of nitric oxide synthase activity (19)(20)(21).…”

Stimulation of 92-kDa Gelatinase B Promoter Activity by ras Is Mitogen-activated Protein Kinase Kinase 1-independent and Requires Multiple Transcription Factor Binding Sites Including Closely Spaced PEA3/ets and AP-1 Sequences

“…The 92-kDa type IV matrix metalloproteinase (92-kDa gelatinase B also known as MMP-9) plays a major role in cell migration in both physiological and pathological processes (1)(2)(3) by facilitating the destruction of the type IV collagencontaining basement membrane which separates the epithelial and stromal compartments (4). The 92-kDa type IV collagenase is secreted as a proenzyme (5) and subsequently activated by multiple enzymes, including cathepsin G, trypsin, stromelysin 1 (6), and 72-kDa gelatinase A (7) by the removal of 73 amino acids from the amino terminus of the protease.…”