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

Although prostaglandin (PG) F-2 alpha. 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-alpha (TNF alpha) and its specific receptors are present in the bovine CL with the highest expressions at luteolysis. TNF alpha in combination with interferon-gamma reduced progesterone (P4) secretion, increased PGF(2 alpha). and leukotriene C-4 (LTC4) production, and induced apoptosis of the luteal cells in vitro. Low concentrations of TNF alpha caused luteolysis, which resulted in a decreased level of P4, and increased levels of PGF(2 alpha), LTC4 and nitrite/nitrate (stable metabolites of nitric oxide-NO) in the blood. Inhibition of local NO production counteracts spontaneous and PGF(2 alpha)-induced luteolysis. Therefore, NO is a likely candidate for the molecule that mediates PGF(2 alpha) and TNF alpha actions during luteolysis. Both PGF(2 alpha) and TNF alpha increase NO concentrations in blood, and stimulate NO synthase expression on protein level in the bovine CL cells. NO stimulates PGF(2 alpha) and LTC4 secretion, inhibits P4 production and reduces the number of viable luteal cells. TNF alpha 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 TNF alpha and NO play crucial roles in functional and structural luteolysis in cattle. (c) 2005 Elsevier Inc. All rights reserved.