Dihydrotestosterone Decreases Tumor Necrosis Factor-α and Lipopolysaccharide-Induced Inflammatory Response in Human Endothelial Cells

• Published in: The journal of clinical endocrinology and metabolism Vol. 91; no. 2; pp. 546 - 554
• Main Authors: Norata, Giuseppe Danilo, Tibolla, Gianpaolo, Seccomandi, Paul Maria, Poletti, Angelo, Catapano, Alberico Luigi
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.02.2006; Copyright by The Endocrine Society
• Subjects: Androgen Antagonists - pharmacology; Androgen Receptor Antagonists; Anilides - pharmacology; Cell Line, Tumor; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - genetics; Dihydrotestosterone - pharmacology; Drug Interactions; E-Selectin - biosynthesis; E-Selectin - genetics; Endothelial Cells - drug effects; Endothelial Cells - immunology; Endothelial Cells - metabolism; Humans; Immunoblotting; Inflammation - drug therapy; Inflammation - metabolism; Intercellular Adhesion Molecule-1 - biosynthesis; Intercellular Adhesion Molecule-1 - genetics; Lipopolysaccharides - pharmacology; NF-kappa B - metabolism; Nitriles; Platelet Endothelial Cell Adhesion Molecule-1 - biosynthesis; Platelet Endothelial Cell Adhesion Molecule-1 - genetics; Receptors, Androgen - immunology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tosyl Compounds; Tumor Necrosis Factor-alpha - pharmacology; Vascular Cell Adhesion Molecule-1 - biosynthesis; Vascular Cell Adhesion Molecule-1 - genetics
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2005-1664

Context: An increasing body of evidence suggests that testosterone may exert beneficial effects on the development of atherosclerosis. It was suggested that testosterone may act after conversion into estradiol and activation of the estrogen receptors; however, a direct role of androgens on the vascular wall has been proposed. Objective: We investigated the effects of dihydrotestosterone on the proinflammatory response observed in human endothelial cells. Design: Human endothelial cells isolated from umbilical cords were incubated with lipopolysaccharide or TNFα in the presence or absence of dihydrotestosterone (DHT). mRNA and cellular proteins were processed for gene expression studies, and transient transfection experiments were performed to investigate molecular mechanisms involved in the effects observed. Setting: These studies took place at the Department of Pharmacological Sciences, University of Milan, Milan, Italy. Results: Lipopolysaccharide and TNFα induced VCAM-1 and ICAM-1 mRNA and protein expression, as detected by real-time quantitative PCR, fluorescence-activated cell sorting, and confocal microscopy, but this effect was inhibited when cells were incubated with DHT. In addition, DHT inhibited mRNA expression of IL-6, MCP-1, CD40, TLR4, PAI-1, and Cox-2 and the release of cytokines and chemokines such as GRO, granulocyte-macrophage colony-stimulating factor, and TNF. The DHT effect was counteracted by bicalutamide, an antagonist of the androgen receptor. Furthermore, when cells were cotransfected with a Cox-2 promoter or a 3X-NF-κB luciferase reporter vector and a plasmid expressing the human androgen receptor, DHT treatment inhibited the increase of the luciferase activity observed with TNFα. Conclusion: DHT could positively regulate endothelial function through the control of the inflammatory response mediated by nuclear factor-κB in endothelial cells.