Epidermal growth factor inhibits cytokine-induced apoptosis of primary human trophoblasts.
In the placenta, as in other organs, the development and maintenance of the differentiated phenotype depend on a balance between cell proliferation, maturation, and death. We are interested in the mechanisms that regulate the survival and differentiation of placental trophoblasts and have recently demonstrated that the inflammatory cytokines tumor necrosis factor alpha (TNF alpha) and gamma interferon (IFN gamma) act in concert to induce apoptotic cell death in normal cytotrophoblasts in culture. In this report we show that exposure to epidermal growth factor (EGF), a 6,700 dalton polypeptide that is abundantly expressed in maternal and fetal tissues, blocks the in vitro TNF/IFN-induced cytotoxicity of human cytotrophoblasts and syncytiotrophoblasts from normal term placentas. This antagonistic effect is dose-related (10-10 M EGF, half-maximal) and proceeds via the interruption of an early step in the cytokine-induced apoptotic response. These observations suggest a novel role for EGF in normal placental development and indicate that the interplay between EGF, TNF alpha, and IFN gamma may determine the rate of trophoblast growth and renewal during gestation.
Garcia-Lloret
M I
MI
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.
Yui
J
J
Winkler-Lowen
B
B
Guilbert
L J
LJ
D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C496453:FGF7 protein, human; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D014409:Tumor Necrosis Factor-alpha; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor