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Soluble Fas Ligand Activates the Sphingomyelin Pathway and Induces Apoptosis in Luteal Steroidogenic Cells Independently of Stress-Activated p38^MAPK

Vincent Center for Reproductive Biology, Massachusetts General Hospital (J.K.P., B.R.R.), Boston, Massachusetts 02114; The Women’s Research Institute (I.R.H., J.S.D.), Wichita, Kansas 67214-3199; Department of Obstetrics and Gynecology, University of Kansas School of Medicine (J.S.D.), Wichita, Kansas 67214-3199; and Veterans Affairs Medical Center (J.S.D.), and Olson Center for Women’s Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center (J.S.D.), Omaha, Nebraska 68105

Address all correspondence and requests for reprints to: Bo R. Rueda, Ph.D., Vincent Center for Reproductive Biology, Massachusetts General Hospital, VBK137E-GYN, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: brueda{at}partners.org.

Fas ligand (FasL) is implicated as a mediator of luteolysis. However, a gap exists in our understanding of the Fas-mediated signaling mechanisms that are involved in either the loss of progesterone production or the structural regression of the corpus luteum. In the present study we investigated the acute and chronic effects of FasL with respect to activation of cytokine/stress-induced signaling pathways and apoptosis in bovine steroidogenic cells. More specifically, we investigated soluble FasL (sFasL)-activated production of ceramide, a second messenger of the sphingomyelin pathway, and activation of p38^MAPK, a member of the MAPK family. sFasL activated the sphingomyelin pathway, as evidenced by a 2-fold increase (P < 0.05) in the production of ceramide. Pretreatment with imipramine (50 µM), an inhibitor of acid sphingomyelinase activity, attenuated (75%; P < 0.05) sFasL-induced ceramide production, suggesting that the increase in ceramide was partially the result of acid sphingomyelinase-mediated hydrolysis of sphingomyelin. Treatment of luteal cells with sFasL or a cell-permeable ceramide analog (C8) for 24–48 h resulted in a significant increase (P < 0.05) in apoptosis. Western blot analysis revealed that sFasL had little effect on the activation of p38^MAPK in primary bovine luteal steroidogenic cells. Furthermore, pretreatment with the p38^MAPK inhibitor SB203580 failed (P > 0.05) to inhibit sFasL- or C8-induced death. Although sFasL did not alter basal progesterone levels detected in the culture medium, C8 caused a significant increase (P < 0.05) in progesterone concentrations within the medium. Collectively, these data suggest that the role of FasL in luteolysis may be to activate the stress-induced sphingomyelin pathway that, in turn, serves as a mediator of apoptosis.

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