Differential regulation of interleukins IL-13 and IL-15 by ovarian steroids, TNF-alpha and TGF-beta in human endometrial epithelial and stromal cells.
Based on the endometrial spatial and temporal expression of interleukins (ILs) IL-13 and IL-15 during the normal menstrual cycle, we hypothesized that ovarian steroids and non-steroidal factors regulate their expression in a cell-specific manner. To test this hypothesis and determine IL-13/IL-15 actions, we used endometrial epithelial (EEC) and stromal (ESC) cells isolated and cultured under defined conditions. We confirmed the expression of IL-13 and IL-15 in these cells and further demonstrated that 17beta estradiol (E2), medroxyprogesterone acetate (MPA) and their combination differentially regulated their mRNA expression and protein production in a time- and cell-specific manner (P < 0.05). We also showed that tumour necrosis factor-alpha (TNF-alpha; 10 and 25 ng/ml) and transforming growth factor-beta (TGF-beta; 1 and 5 ng/ml), cytokines with inflammatory and immune regulatory functions in a cell- and dose-dependent manner regulate the expression of IL-13 and IL-15 (P < 0.05). Functionally, IL-13 and IL-15 1-100 ng/ml displayed a limited mitogenic activity towards EEC and ESC; however, they regulated the expression of TNF receptor type 1 (TNFR) mRNA and soluble protein in a cell-specific manner (P < 0.05). We conclude that ovarian steroids, TNF-alpha and TGF-beta act as key regulators of endometrial IL-13 and IL-15 expression which act locally regulating TNFR expression in a cell-specific manner. Based on these findings, we conclude that IL-13/IL-15, either alone or through their interactions with other cytokines, influence the outcome of endometrial inflammatory/immune responses during the normal menstrual cycle, and due to their altered expression may extend these processes in dysfunctional bleeding and endometriosis.
Roberts
Marisa
M
Department of Obstetrics & Gynecology, University of Florida College of Medicine, Gainesville, FL 32610-0294, USA.
Luo
Xiaoping
X
Chegini
Nasser
N
D000328:Adult; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008597:Menstrual Cycle / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D012739:Gonadal Steroid Hormones; D018793:Interleukin-13; D019409:Interleukin-15; D047888:Receptors, Tumor Necrosis Factor, Type I; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D017258:Medroxyprogesterone Acetate