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 C₄ (LTC₄) 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, LTC₄ 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 LTC₄ 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.