EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA ON LUTEINIZING HORMONE-STIMULATED PRORENIN PRODUCTION BY BOVINE OVARIAN THECAL CELLS IN-VITRO

Investigations have been carried out to determine if the cytokine tumor necrosis factor-alpha (TNFalpha), a putative intraovarian regulator, Plays a role in the regulation of the ovarian prorenin-renin-angiotensin system. Addition of TNFalpha to cultured bovine thecal cells resulted in a dose-dependent inhibition of LH- or 8-bromo-cAMP-stimulated production of prorenin and renin by the cells in a noncytotoxic manner. No clear inhibitory effect on progesterone production was noted. There was no inhibition of LH- or forskolin-stimulated cAMP formation by TNFalpha. The time-course experiment with TNFalpha revealed that the synthesis, rather than the secretion, of prorenin was inhibited. Also, it was evident that to observe a maximal inhibitory effect, it was necessary to add TNFalpha either before or together with LH. With the increasing delay in the addition of TNFalpha relative to the time of addition of LH, the extent of inhibition gradually decreased, and TNFalpha added 6 h after the addition of LH failed to produce any inhibitory effect. The results obtained permit us to conclude that TNFalpha can counterregulate LH-stimulated prorenin production by thecal cells in culture. The TNFalpha-induced lesion appears to be located at an early step of the biosynthetic pathway of prorenin, which is distal to the activation of LH receptor-coupled adenylate cyclase. Thus, this cytokine appears to be an important intraovarian regulator of prorenin production, a process that is under the stimulatory control of the pituitary gonadotropin.