CYTOKINE-MEDIATED REGULATION OF RAT OVARIAN-FUNCTION - INTERLEUKIN-1 INHIBITS PLASMINOGEN-ACTIVATOR ACTIVITY THROUGH THE INDUCTION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 (PAI-1)

Intraovarian IL-1 has recently been implicated as a mediator in the ov ulatory process. Since PA activation is an established component of th e ovulatory cascade, consideration was given in this report to the pos sibility that IL-1 may modulate ovarian PA economy. Whole ovarian disp ersates from immature rats (25-27-days-old) were cultured under serum- free conditions for 48 h in the absence or presence of IL-1 beta. Cell ular PA activity was measured by plasminogen-dependent cleavage of C-1 4-labeled globin. Cells grown in the absence of IL-1 exhibited appreci able PA activity, as assessed by the cleavage of 0.074 +/- 0.026 mg [C -14]-globin/5 x 10(5) cells (mean +/- SD). Exposure to IL-1 (10 ng/ml) led to a 30% reduction in cell-associated PA activity (p < 0.001). Th e IL-1-mediated inhibition occurred concurrently with a 10-fold increa se in the ability of the corresponding conditioned media to inhibit ex ogenous urokinase activity. At similar cell densities of 5 x 10(5) cel ls/well, isolated cultures of theca and granulosa cells exhibited comp arable PA activity in the absence of IL-1. However, only theca cells r esponded to IL-1 with inhibition of plasminogen activation and enhance ment of urokinase inhibitory activity. Granulosa cells in turn failed to respond to IL-1. Both the inhibition of PA activity and the increas e in urokinase inhibitory activity proved cell-density- and IL-1 dose- dependent. The IL-1-induced inhibition of urokinase was abolished by t he administration of a polyclonal anti-rat PAI-1 IgG. Both effects of IL-1 were counteracted in a dose-dependent fashion by the soluble IL-1 receptor (which specifically complexes with IL-1), and by a highly-sp ecific IL-1 receptor antagonist suggesting that the IL-1 effects are r eceptor-mediated. The present observations indicate that ovarian PA ac tivity is subject to inhibition by IL-1 probably by way of PAI-1 of th eca-interstitial origin. Inasmuch as IL-1 may be involved in initiatin g and maintaining the preovulatory cascade, the periovulatory activati on of plasminogen must be accomplished by agents other than IL-1.