Effect of TNF-α on Estrogen Metabolism and Endometrial Cells: Potential Physiological and Pathological Relevance

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2009-01, Vol.23 (1), p.124-124
• Main Authors: Salama, Salama A, Kamel, Marwa W, Diaz-Arrastia, Concepcion R, Xu, Xia, Veenstra, Timothy D, Salih, Sana, Botting, Shaleen K, Kumar, Raj
• Format: Article
• Language: English
• Subjects: Translational Highlights from Jcem
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/mend.23.1.9999

Abstract Context Estrogen and its metabolites play a critical role in the pathophysiology of the endometrium. The bioavailability of estrogen and estrogen metabolites in endometrial tissues depends on the expression of enzymes involved in estrogen biosynthesis and metabolism. Substantial evidence indicates that estrogen-dependent endometrial disorders are also associated with proinflammatory milieu. However, the mechanism whereby inflammation contributes to these conditions is not known. Objective Investigate the effect of the tumor necrosis factor-α (TNF-α) on estrogen metabolism and on the expression of estrogen-metabolizing genes in human endometrial glandular epithelial cells (EM1). Design EM1 were treated with 17β-estradiol (E2) with or without TNF-α. Capillary liquid chromatography-tandem mass spectrometry analysis was used for quantitative measurement of estrogens and estrogen metabolites. Western blot analysis, reporter gene assay, and real time RT-PCR were used to assess the expression of estrogen-metabolizing genes. Results TNF-α treatment significantly increased the level of total estrogen and estrogen metabolites and significantly increased the rate of conversion of estrone (E1) into E2. TNF-α also enhanced the oxidative metabolism of estrogen into catecholestrogens with concomitant inhibition of their conversion into methoxyestrogens. Gene expression analysis revealed that TNF-α induced the expression of genes involved in E2 biosynthesis (SF-1 and CYP19) and activation (HSD17B1 and CYP1B1) with simultaneous repression of genes involved in estrogen inactivation (HSD17B2; COMT; and NQO1). Conclusion TNF-α increases the local estrogen biosynthesis in human endometrial glandular cells and directs estrogen metabolism into more hormonally active and carcinogenic metabolites. These effects may impact many physiological and pathological processes that occur within endometrium.