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 ovulatory process. Since PA activation is an established component of the ovulatory cascade, consideration was given in this report to the possibility that IL-1 may modulate ovarian PA economy. Whole ovarian dispersates from immature rats (25-27-days-old) were cultured under serum-free conditions for 48 h in the absence or presence of IL-1beta. Cellular PA activity was measured by plasminogen-dependent cleavage of 14C-labeled globin. Cells grown in the absence of IL-1 exhibited appreciable PA activity, as assessed by the cleavage of 0.074 +/- 0.026 mg [14C]-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). The IL-1-mediated inhibition occurred concurrently with a 10-fold increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. At similar cell densities of 5 x 10(5) cells/well, isolated cultures of theca and granulosa cells exhibited comparable PA activity in the absence of IL-1. However, only theca cells responded to IL-1 with inhibition of plasminogen activation and enhancement of urokinase inhibitory activity. Granulosa cells in turn failed to respond to IL-1. Both the inhibition of PA activity and the increase in urokinase inhibitory activity proved cell-density- and IL-1 dose-dependent. The IL-1-induced inhibition of urokinase was abolished by the 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-specific IL-1 receptor antagonist suggesting that the IL-1 effects are receptor-mediated. The present observations indicate that ovarian PA activity is subject to inhibition by IL-1 probably by way of PAI-1 of theca-interstitial origin. Inasmuch as IL-1 may be involved in initiating and maintaining the preovulatory cascade, the periovulatory activation of plasminogen must be accomplished by agents other than IL-1.
Hurwitz
A
A
Department of Obstetrics / Gynecology, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel.
Finci-Yeheskel
Z
Z
Dushnik
M
M
Milwidsky
A
A
Ben-Chetrit
A
A
Yagel
S
S
Adashi
E Y
EY
Mayer
M
M
D000818:Animals; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D005260:Female; D007375:Interleukin-1 / Q000494:pharmacology*; D010053:Ovary / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D010960:Plasminogen Activators / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D016895:Culture Media, Serum-Free; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D010960:Plasminogen Activators