Induction of apoptosis in granulosa cells by TNFα and its attenuation by glucocorticoids involve modulation of Bcl-2

Tumor necrosis factor alpha (TNFalpha) plays a role in mammalian ovarian follicular development, steroidogenesis, ovulation, luteolysis, and atresia, but the exact mechanism of TNFalpha action is not completely understood. Induction of apoptosis and suppression of steroidogenesis by TNFalpha in primary preovulatory rat and human granulosa cells, as well as, in human granulosa cells immortalized by mutated p53, were characterized in the present work. Dexamethasone (Dex) and hydrocortisone efficiently suppressed TNFalpha-induced apoptosis in granulosa cells. TNFalpha dramatically reduced intracellular levels of Bcl-2, while Dex abrogated this reduction. TNFalpha reduced considerably intracellular levels of StAR protein, a key regulating factor in steroidogenesis. This reduction can be explained only in part by elimination of cells through apoptosis., since loss of steroidogenic capacity was much higher and faster than the rate and extent of loss of cell viability induced by TNFalpha, suggesting independent mechanisms for TNFalpha-induction of apoptosis and TNFalpha-suppression of steroidogenesis. (C) 2002 Elsevier Science (USA). All rights reserved.