INTERLEUKIN-1-MEDIATED REGULATION OF PLASMINOGEN ACTIVATION IN PREGNANT MARE SERUM GONADOTROPIN-PRIMED RAT GRANULOSA-CELLS IS INDEPENDENT OF PROSTAGLANDIN PRODUCTION

OBJECTIVES: This study examiner the effects of interleukin-1 (IL-1) on plasminogen activator (PA) activity and prostaglandin (PG) E producti on in pregnant mare serum gonadotropin (PMSG)-primed granulosa cells a nd the potential involvement of PGE in the vegulation of ovarian plasm inogen activation. METHODS: Granulosa cells were obtained from PMSG-pr imed rat (27-day-old) ovaries and cultured in serum-free conditions fo r 48 hours in the absence or presence of IL-1 beta (10 ng/mL) with and without transforming growth factor-beta 1 (10 ng/mL). Cellular PA act ivity was measured through the conversion of plasminogen to plasmin an d assay of the plasmin-mediated cleavage of [C-14]-labeled globin to a cid-soluble products. RESULTS: Exposure of PMSG-primed granulosa cells to IL-1 resulted in a 30% reduction (P < .05) in PA activity. Additio n of hCG (1 IU/mL) to the granulosa cell cultures resulted in a 2.3-fo ld increase in PA activity, an effect significantly attenuated by co-a dministration of IL-1. The IL-1-mediated inhibition occurred concurren t with a 6.6-fold increase in the ability of the corresponding conditi oned media to inhibit exogenous urokinase activity. This latter inhibi tory capacity was the result of a significant increase in plasminogen activator inhibitor type 1 (PAI-1), given its abolition by a polyclona l anti-rat PAI-1 immunoglobulin G. The IL-1-mediated effects on PA/PAI -1 were accompanied by a sevenfold increase in PGE content of the spen t culture medium. This response war dose dependent. The IL-1 effects o n plasminogen activation and PG production were abolished by the IL-1 receptor antagonist, suggesting specific IL-1 receptor-mediated respon ses. Indomethacin, an inhibitor of PG biosynthesis, prevented the IL-1 -induced increase in PGE accumulation but failed to affect the respons e of the PA system, Transforming growth factor-beta 1, a known regulat or of IL-1 action, significantly attenuated the IL-1-stimulated PGE pr oduction but did not interfere with the ability of IL-1 to affect the PA system. CONCLUSIONS: The present observations suggest a pleiotropic response of PMSG-primed granulosa cells to IL-1, characterized by the induction of PAI-1 concurrent with but independent of PG production. These findings corroborate and extend earlier observations suggesting that IL-1 affects PA activity and PGE production in immature vat ovari es. Moreover, these observations support our contention that IL-1 may play a major regulatory role in the cellular events leading to ovulati on and early corpus luteum formation.