EFFECTS OF CYTOKINES ON PROSTAGLANDIN PRODUCTION AND STEROIDOGENESIS OF INCUBATED PREOVULATORY FOLLICLES OF THE RAT

Cytokines, leukocyte-derived peptide regulators of inflammation and other lympho-hematopoeitic processes, have been implicated in ovarian physiology on the basis of findings of cytokines in follicular fluids and the presence of leukocytes in ovarian tissue. During the dramatic tissue remodelling at ovulation, several inflammatory mediators play pivotal roles in the occurrence of follicular rupture, but no data exist regarding the involvement of cytokines in this process. In the present study we have examined the effects of three different lymphocyte- and macrophage-derived cytokines-tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and interleukin-2 (IL-2)-on the production of ovulatory mediators such as prostaglandins and progesterone in the preovulatory follicle of the eCG/hCG-primed immature rat. Preovulatory follicles were incubated in the presence of human recombinant cytokines for up to 24 h, and the concentrations of prostaglandins and steroids in the incubation medium were measured by RIAs. TNFalpha and IL-1beta stimulated production of prostaglandin E and prostaglandin F2alpha in a dose-dependent manner during a 24-h incubation. Synthesis of prostacyclin was also stimulated by TNFalpha and IL-1beta, as indicated by high levels of its stable metabolite 6-keto-prostaglandin F1alpha. Time-course studies showed that a major portion of the prostaglandins were produced between 12 and 24 h. IL-2 was without effect on these parameters. TNFalpha and IL-1beta also dose-dependently increased the production of progesterone and this was not inhibited by indomethacin. The levels of androstenedione and estradiol were not significantly increased by TNFalpha or IL-1beta. IL-2 did not affect steroidogenesis. The TNFalpha- and IL-beta-induced increase in prostaglandin and progesterone production was not evident in granulosa cell cultures but in cultures of thecal tissues, indicating that the major effects of TNFalpha and IL-1beta were on the thecal/interstitial cells. The presence of leukocytes in the preovulatory rat ovary together with the observed stimulatory effects on ovulatory mediators such as prostaglandins and progesterone by TNFalpha and IL-1beta indicates that these cytokines may play physiological roles in the inflammation-like process of ovulation.