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 tumo r necrosis factor-alpha (TNFalpha), a putative intraovarian regulator, Plays a role in the regulation of the ovarian prorenin-renin-angioten sin system. Addition of TNFalpha to cultured bovine thecal cells resul ted in a dose-dependent inhibition of LH- or 8-bromo-cAMP-stimulated p roduction of prorenin and renin by the cells in a noncytotoxic manner. No clear inhibitory effect on progesterone production was noted. Ther e was no inhibition of LH- or forskolin-stimulated cAMP formation by T NFalpha. The time-course experiment with TNFalpha revealed that the sy nthesis, rather than the secretion, of prorenin was inhibited. Also, i t was evident that to observe a maximal inhibitory effect, it was nece ssary to add TNFalpha either before or together with LH. With the incr easing delay in the addition of TNFalpha relative to the time of addit ion of LH, the extent of inhibition gradually decreased, and TNFalpha added 6 h after the addition of LH failed to produce any inhibitory ef fect. The results obtained permit us to conclude that TNFalpha can cou nterregulate LH-stimulated prorenin production by thecal cells in cult ure. The TNFalpha-induced lesion appears to be located at an early ste p of the biosynthetic pathway of prorenin, which is distal to the acti vation of LH receptor-coupled adenylate cyclase. Thus, this cytokine a ppears to be an important intraovarian regulator of prorenin productio n, a process that is under the stimulatory control of the pituitary go nadotropin.