title: Tumor necrosis factor-α activates estrogen signaling pathways in endometrial epithelial cells via estrogen receptor α.
abstract: The pro-inflammatory cytokine TNF-α and the female hormone estrogen have been implicated in the pathophysiology of two common gynecological diseases, endometriosis and endometrial adenocarcinoma. Here we describe a novel capacity of TNF-α to activate ER signaling in endometrial epithelial cells. TNF-α induced luciferase expression in the absence and presence of estradiol and also augmented expression of the estrogen-regulated genes c-fos, GREB1, and progesterone receptor. Furthermore, TNF-α mediated ER transcriptional activity is dependent on the Extracellular Regulated Kinase (ERK) 1/2 pathway. Co-treatment with a pure ER antagonist resulted in an inhibition of this TNF-α-induced ERE luciferase activity and gene expression, demonstrating that this cytokine signals through ERs. Additional investigations confirmed that TNF-α acts specifically via ERα. Taken together, these data provide a rationale for the potential use of inhibitors of TNF-α and estrogen production/activity in combination for the treatment of endometrial pathologies.
authors.affiliation: Mucosal Immunity Laboratory, Dept. of Gynecology, Obstetrics and Medical Genetics, University Hospital Center, University of Lausanne, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Gori
authors.forename: Chiara
authors.initials: C
authors.lastname: Pellegrini
authors.forename: Davide
authors.initials: D
authors.lastname: Staedler
authors.forename: Ronan
authors.initials: R
authors.lastname: Russell
authors.forename: Caroline
authors.initials: C
authors.lastname: Jan
authors.forename: Geraldine O
authors.initials: GO
authors.lastname: Canny
mesh_terms: D002460:Cell Line; D004717:Endometrium / Q000166:cytology*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha; D010768:Phosphoserine; D004958:Estradiol; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases