title: Estradiol modulates tumor necrosis factor-induced endothelial inflammation: role of tumor necrosis factor receptor 2.
abstract: The sex hormone estradiol (E(2)) appears to mediate both anti-atherogenic and pro-inflammatory effects in premenopausal women, suggesting a complex immunomodulatory role. Tumor necrosis factor (TNF) is a key pro-inflammatory cytokine involved in the pathogenesis of atherosclerosis and other inflammatory diseases. Alterations at the TNF receptors (TNFRs) and their downstream signaling/transcriptional pathways can affect inflammatory responses. Given this background, we hypothesized that chronic E(2) exposure would alter endothelial inflammatory response involving modulation at the levels of TNFRs and signaling pathways. HUVECs were used as the model system. Pre-treatment with E(2) did not significantly alter TNF-induced upregulation of pro-inflammatory molecules ICAM-1 (3-6 times) and VCAM-1 (5-7 times). However, pharmacological inhibition of transcriptional pathways suggested a partial shift from NF-ĸB (from 97 to 64%) towards the JNK/AP-1 pathway in ICAM-1 upregulation on E(2) treatment. In contrast, VCAM-1 expression remained NF-ĸB dependent in both control (∼96%) and E(2) treated (∼85%) cells. The pro-inflammatory TNF effects were mediated by TNFR1. Interestingly, E(2) pre-treatment increased TNFR2 levels in these cells. Concomitant TNFR2 activation (but not TNFR1 activation alone) led to the shift towards JNK/AP-1-mediated ICAM-1 upregulation in E(2)-treated cells, suggesting the effects of chronic E(2) to be dependent on TNFR2 signaling.
authors.affiliation: Departments of Obstetrics and Gynecology and Physiology, Women and Children's Health Research Institute, Cardiovascular Research Center and Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alta., Canada.
authors.forename: Subhadeep
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
mesh_terms: D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases