INTERACTIONS BETWEEN INTERFERON-GAMMA, TUMOR-NECROSIS-FACTOR-ALPHA, AND INTERLEUKIN-1 IN MODULATING PROGESTERONE AND ESTRADIOL PRODUCTION BY HUMAN LUTEINIZED GRANULOSA-CELLS IN CULTURE

We have reported that the cytokines, interleukin-1 (IL-1), tumour necrosis factor alpha (TNFalpha), and interferon (IFN)alpha, beta, and gamma modulate the steroidogenic function of human luteinized granulosa cells in culture. In the present study we examined the interactions between these cytokines in modulating progesterone and oestradiol production by these cells. Neither IL-1 nor TNFalpha had significant effects on human chorionic gonadotrophin (HCG)-stimulated progesterone production, whereas IFNgamma (1 - 10 ng/ml) significantly reduced HCG-stimulated progesterone production by 26-37%. Concomitant treatment with IL-1 (I ng/ml) did not further enhance the inhibitory effect of IFNgamma on HCG-stimulated progesterone production. In contrast, the combination of TNFalpha (1 ng/ml) and IFNgamma (10 ng/ml) acted synergistically to markedly inhibit HCG-stimulated progesterone production by 81%. In addition, IL-1 and TNFalpha, neither of which was effective alone, acted synergistically to reduce significantly HCG-stimulated progesterone production by 30%. The combination of TNFalpha and IFNgamma also markedly inhibited follicle stimulating hormone (FSH)-stimulated oestradiol production by 97%, a significantly greater inhibition than that obtained with either cytokine alone. These results suggest that the cytokines may interact to modulate the steroidogenic function of luteal cells in the developing corpus luteum.