Soluble Fas ligand activates the sphingomyelin pathway and induces apoptosis in luteal steroidogenic cells independently of stress-activated p38MAPK

James K. Pru, Isabel R. Hendry, John S Davis, B. R. Rueda

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 p38MAPK, 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 p38MAPK in primary bovine luteal steroidogenic cells. Furthermore, pretreatment with the p38MAPK inhibitor SB203580 failed (P > 0.05) to inhibit sFasL- or CS-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.

Original languageEnglish (US)
Pages (from-to)4350-4357
Number of pages8
JournalEndocrinology
Volume143
Issue number11
DOIs
StatePublished - Nov 1 2002

Fingerprint

Luteal Cells
Fas Ligand Protein
Sphingomyelins
Luteolysis
Apoptosis
Progesterone
Ceramides
Second Messenger Systems
Culture Media
Cytokines

ASJC Scopus subject areas

  • Endocrinology

Cite this

Soluble Fas ligand activates the sphingomyelin pathway and induces apoptosis in luteal steroidogenic cells independently of stress-activated p38MAPK. / Pru, James K.; Hendry, Isabel R.; Davis, John S; Rueda, B. R.

In: Endocrinology, Vol. 143, No. 11, 01.11.2002, p. 4350-4357.

Research output: Contribution to journalArticle

@article{8a646907208d48c689574f32d07f89c4,
title = "Soluble Fas ligand activates the sphingomyelin pathway and induces apoptosis in luteal steroidogenic cells independently of stress-activated p38MAPK",
abstract = "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 p38MAPK, 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 p38MAPK in primary bovine luteal steroidogenic cells. Furthermore, pretreatment with the p38MAPK inhibitor SB203580 failed (P > 0.05) to inhibit sFasL- or CS-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.",
author = "Pru, {James K.} and Hendry, {Isabel R.} and Davis, {John S} and Rueda, {B. R.}",
year = "2002",
month = "11",
day = "1",
doi = "10.1210/en.2002-220229",
language = "English (US)",
volume = "143",
pages = "4350--4357",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "11",

}

TY - JOUR

T1 - Soluble Fas ligand activates the sphingomyelin pathway and induces apoptosis in luteal steroidogenic cells independently of stress-activated p38MAPK

AU - Pru, James K.

AU - Hendry, Isabel R.

AU - Davis, John S

AU - Rueda, B. R.

PY - 2002/11/1

Y1 - 2002/11/1

N2 - 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 p38MAPK, 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 p38MAPK in primary bovine luteal steroidogenic cells. Furthermore, pretreatment with the p38MAPK inhibitor SB203580 failed (P > 0.05) to inhibit sFasL- or CS-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.

AB - 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 p38MAPK, 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 p38MAPK in primary bovine luteal steroidogenic cells. Furthermore, pretreatment with the p38MAPK inhibitor SB203580 failed (P > 0.05) to inhibit sFasL- or CS-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.

UR - http://www.scopus.com/inward/record.url?scp=0036828188&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036828188&partnerID=8YFLogxK

U2 - 10.1210/en.2002-220229

DO - 10.1210/en.2002-220229

M3 - Article

C2 - 12399431

AN - SCOPUS:0036828188

VL - 143

SP - 4350

EP - 4357

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 11

ER -