Receptor-mediated stimulatory effect of IL-1 beta on hyaluronic acid and proteoglycan biosynthesis by cultured rat ovarian cells: role for heterologous cell-cell interactions.

An increasing body of information supports the possibility that intraovarian interleukin (IL)-1 may play an intermediary role in gonadotropin-triggered ovulation. To further evaluate this hypothesis, we have examined the effect of IL-1 beta on ovarian proteoglycan/glycosaminoglycan economy, an established corollary of the preovulatory cascade. Rat ovarian cells were metabolically labeled with [35S]sulfate and [3H]glucosamine for 48h in the absence or presence of IL-1 beta, with or without an IL-1 receptor antagonist (IL-1ra). At the conclusion of this treatment period, total 35S and 3H incorporation into cell-associated and extracellular proteoglycan/glycosaminoglycan species was determined. Treatment of whole ovarian dispersates with IL-1 beta (10 ng/ml) produced substantial increments in the accumulation of extracellular macromolecular material [11.5-, 2.9- and 2.6-fold for hyaluronic acid (HA), heparan sulfate (HS) and dermatan sulfate (DS) proteoglycans, respectively]. In contrast, only modest increments (< or = 1.7-fold) were noted for IL-1 beta-treated granulosa cells (GC), theca-interstitial cells (TC), or 4:1 co-cultures (GC/TC) thereof. Treatment of whole ovarian dispersates with IL-1 beta also resulted in significant (P < 0.001) increments in the cell-associated accumulation of both HA (6.0-fold increase) and DS proteoglycans (3.4-fold increase). However, the cell-associated accumulation of HS proteoglycan was not significantly affected by IL-1 beta regardless of the cellular preparation under study. The concurrent provision of IL-1ra (5 micrograms/ml) all but neutralized the IL-1 beta effect on HA biosynthesis thereby suggesting mediation by specific ovarian IL-1 receptor(s). Taken together, these observations suggest that treatment of ovarian cells with IL-1 beta results in an overall increase in macromolecular biosynthesis as well as in redistribution favoring extracellular HA and DS (but not HS) proteoglycans. Moreover, since whole ovarian dispersates proved more responsive to IL-1 than isolated cellular components thereof, the present observations suggest an obligatory requirement for heterologous cell-cell interaction without which optimal HA or proteoglycan biosynthesis may not be realized. These observations along with the demonstration of IL-1-mediated amplification of gonadotropin-triggered ovulation provide strong indirect support for the view that IL-1 may be the centerpiece of an intraovarian regulatory loop concerned with the promotion of key periovulatory events.