Role of tumor necrosis factor-alpha in the ovulatory mechanism of ewes.

Tumor necrosis factor (TNF)-alpha was localized by indirect immunofluorescence microscopy to thecal endothelial cells or preovulatory ovine follicles. Immunostaining of endothelial cells within the apical hemisphere of the follicle declined abruptly with the approach of ovulation; cells within the counterpart basal follicular wall remained largely unaffected. It appeared that TNF alpha had been released into the presumptive area of follicular rupture. Intrafollicular injection of TNF alpha antiserum blocked ovulation in ewes. We considered the possibility that TNF alpha liberated from apical endothelial cells mediates the programmed deletion of ovarian surface and follicular cells that occurs within the formative ovulatory stigma of sheep. Indeed, contiguous ovarian surface epithelium, thecal endothelium, and granulosal cells were protected from apoptotic death (DNA fragmentation) by exposure to TNF alpha antibodies. Finally, TNF alpha induced ovarian cell apoptosis in vitro. We suggest that a bioactive, soluble form of TNF alpha generated from endothelial cells of preovulatory ovine follicles has an obligatory role in the biomechanics of apical follicular weakening and ovarian rupture.