Role of tumor necrosis factor-α and nitric oxide in luteolysis in cattle

Although prostaglandin (PG) F 2α is known to be a principal luteolytic factor, its action on the bovine corpus luteum (CL) is mediated by other intra-ovarian factors. Tumor necrosis factor-α (TNFα) and its specific receptors are present in the bovine CL with the highest expressions at luteolysis. TNFα in combination with interferon-γ reduced progesterone (P4) secretion, increased PGF 2α and leukotriene C 4 (LTC 4) production, and induced apoptosis of the luteal cells in vitro. Low concentrations of TNFα caused luteolysis, which resulted in a decreased level of P4, and increased levels of PGF 2α, LTC 4 and nitrite/nitrate (stable metabolites of nitric oxide-NO) in the blood. Inhibition of local NO production counteracts spontaneous and PGF 2α-induced luteolysis. Therefore, NO is a likely candidate for the molecule that mediates PGF 2α and TNFα actions during luteolysis. Both PGF 2α and TNFα increase NO concentrations in blood, and stimulate NO synthase expression on protein level in the bovine CL cells. NO stimulates PGF 2α and LTC 4 secretion, inhibits P4 production and reduces the number of viable luteal cells. TNFα and NO induce apoptotic death of the CL by modulating expression of bcl-2 family genes and by stimulating expression and activity of caspase-3. The above findings indicate that TNFα and NO play crucial roles in functional and structural luteolysis in cattle.