Interleukin-1-mediated stimulation of prostaglandin E production is without effect on plasminogen activator activity in human granulosa lutein cell cultures.
In continuation of earlier observations on the involvement of interleukin-1 (IL-1) in ovarian function, we examined the ability of IL-1 to modulate plasminogen activator (PA) activity and prostaglandin (PG) synthesis in human granulosa lutein cells (GLCs). Toward this goal, GLCs were obtained from women undergoing in vitro fertilization, preincubated with 10% fetal calf serum for 48 h, and subsequently cultured for 48 h in serum-free media in the absence or presence of IL-1 beta (10 ng/mL). Cellular PA activity was measured by plasminogen-dependent cleavage of the chromogenic substrate H-D-valyl-L-leucyl-L-lysine-p-nitroanilide (S-2251). Prostaglandin E (PGE) levels were assayed by conventional RIA. Exposure of GLCs to IL-1 resulted in a 50% increase in PGE production, a 33% suppression of PA activity, and a 75% increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. The inhibitory capacity was attributable to an IL-1-mediated increase in PA inhibitor type-1 (PAI-1) production, inasmuch as urokinase inhibition could be abolished by the administration of a polyclonal antihuman PAI-1 immunoglobulin G. IL-1 treatment had no effect on plasmin or trypsin inhibition. Exposure of GLCs to IL-1 receptor antagonist abolished the ability of IL-1 to enhance PA inhibitory activity and PGE production, thereby establishing specific IL-1 receptor-mediated effects. The ability of IL-1 to suppress PA activity and to produce PAI-1 persisted in the presence of indomethacin, a potent inhibitor of PG synthesis. Likewise, transforming growth factor-beta 1 suppressed the ability of IL-1 to stimulate PGE production without affecting the IL-1-induced effects on the PA system. The present findings suggest a pluripotent response of GLCs to IL-1, characterized by the induction of PAI-1 and the suppression of PA occurring concurrent with, but independent of, PG production. These observations support the potential involvement of IL-1 in the regulation of human ovulatory processes.
Hurwitz
A
A
Department of Obstetrics/Gynecology, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel.
Lavy
Y
Y
Finci-Yeheskel
Z
Z
Milwidsky
A
A
Shimonovitz
S
S
Yagel
S
S
Adashi
E Y
EY
Laufer
N
N
Mayer
M
M
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D003338:Corpus Luteum / Q000502:physiology; D016895:Culture Media, Serum-Free; D005260:Female; D005307:Fertilization in Vitro; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010060:Ovulation; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000096:biosynthesis / Q000494:pharmacology; D010960:Plasminogen Activators / Q000378:metabolism*; D011458:Prostaglandins E / Q000378:metabolism*; D011863:Radioimmunoassay; D012795:Sialoglycoproteins / Q000494:pharmacology; D013379:Substrate Specificity; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D016895:Culture Media, Serum-Free; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D011458:Prostaglandins E; D012795:Sialoglycoproteins; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator