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Role of Tumor Necrosis Factor-Alpha and the Modulating Effect of the Caspases in Rat Corpus Luteum Apoptosis¹

^a School of Anatomy and Human Biology, The University of Western Australia, Crawley, Western Australia 6009, Australia, and the West Australian Institute of Medical Research, Sir Charles Gairdner Hospital, Shenton Park, Western Australia 6008, Australia

Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine that has been implicated in apoptosis of many cell systems. However, the signal transduction of TNF during the structural and functional regression of the corpus luteum (CL) is largely unknown. In this study, we investigate the role of TNF in rat CL apoptosis and the involvement of monocyte chemoattractant protein-1 (MCP-1) and the modulating effect of the caspases in this process. An in vivo study of CL during pregnancy and postpartum using immunohistochemistry and Western blot analysis indicated that increases in TNF correspond with luteal apoptosis approaching term (Day 22) and at postpartum (Day 3). CL apoptosis was further investigated using a whole-CL culture model of tropic withdrawal. An increase was observed in both low molecular weight (MW) DNA fragmentation and TUNEL staining from 0 h to 8 h in culture. CL apoptosis in vitro was associated with increased protein expression of both TNF and MCP-1 as measured by immunohistochemistry and Western blot analysis. Using a whole-CL culture model, apoptosis was induced in vitro by TNF as demonstrated by a dose-dependent increase in DNA fragmentation. Treatment of luteal cells with TNF and both specific caspase inhibitors (Z-DEVD-FMK, Z-VEID-FMK, Z-IETD-FMK) or a general caspase inhibitor (Boc-D-FMK) prevented the effect of TNF. CL regression involves the apoptotic deletion of luteal cells; the results of this study suggest that TNF is possibly involved in this process. The observed increases in MCP-1 expression suggest the coordination of TNF expression with the infiltration and activation of macrophages. Furthermore, the results demonstrate the importance of the caspases in the TNF signal transduction pathway and suggest a hierarchy within the caspase family.

¹ This work was supported by grants received from The National Health and Medical Research Council of Australia, Australian Research Council, and the Raine Foundation.

² Correspondence: A.M. Dharmarajan, School of Anatomy and Human Biology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia. FAX: 61 0 8 9380 1051; dharma{at}anhb.uwa.edu.au