https://scholars.lib.ntu.edu.tw/handle/123456789/458225
標題: | The role of IL-6 trans-signaling in vascular leakage: Implications for ovarian hyperstimulation syndrome in a murine model | 作者: | LING-HUNG WEI Chou C.-H Chen M.-W Rose-John S Kuo M.-L SHEE-UAN CHEN YU-SHIH YANG |
公開日期: | 2013 | 卷: | 98 | 期: | 3 | 起(迄)頁: | E472-E484 | 來源出版物: | Journal of Clinical Endocrinology and Metabolism | 摘要: | Context: The inflammatory cytokine IL-6 is related to ovarian hyperstimulation syndrome (OHSS), although the functional role of IL-6 in OHSS remains largely unknown. Objective: A key feature of the IL-6 response is that its regulation is dependent on IL-6 trans-signaling via soluble IL-6 receptor-α (sIL-6Rα). The objective of the study was to elucidate the mechanistic role of IL-6 trans-signaling in the vascular leakage that underlies the pathophysiology of OHSS. Design: Ovarian endothelial cells (ECs) and granulosa-lutein cells were obtained from women undergoing in vitro fertilization. OHSS was induced in mice by administering gonadotropins for 2 days followed by human chorionic gonadotropin. The functional role of IL-6 trans-signaling in OHSS was verified using the designer cytokines Hyper IL-6 and sgp130-Fc. Results: The follicular fluid levels of sIL-6Rα were elevated in women at high risk for OHSS. In the murine OHSS model, stimulation with gonadotropins significantly induces ovarian IL-6 and sIL-6Rα expression. In vitro, FSH induces de novo sIL-6Rα synthesis in granulosa-lutein cells through a protein kinase C-dependent pathway. In addition, sIL-6Rα was released by leukocytes in the presence of conditioned medium from human chorionic gonadotropin-treated granulosa-lutein cells. Ovarian ECs responded to the IL-6Rα-IL-6 complex (Hyper IL-6) but not to IL-6 alone. With activation of signal transducer and activator of transcription 3 (STAT3) and ERK, Hyper IL-6 increased vascular endothelial growth factor expression and the vascular permeability of ECs. Selective blockade of IL-6 trans-signaling by sgp130-Fc significantly inhibited vascular endothelial growth factor expression and prevented OHSS in mice. Conclusions: IL-6 trans-signaling is activated during the ovarian stimulation process. Our findings provide insight into the biologic effects of IL-6 trans-signaling in OHSS and highlight that IL-6 trans-signaling can induce vascular leakage in this disease. Copyright ? 2013 by The Endocrine Society. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/458225 | ISSN: | 0021-972X | DOI: | 10.1210/jc.2012-3462 | SDG/關鍵字: | interleukin 6; interleukin 6 receptor alpha; mitogen activated protein kinase; protein kinase C; soluble interleukin 6 receptor alpha; STAT3 protein; unclassified drug; vasculotropin; adult; animal experiment; animal model; animal tissue; article; blood vessel permeability; controlled study; endothelium cell; female; granulosa cell; human; human cell; in vitro study; luteal cell; major clinical study; nonhuman; ovary hyperstimulation; pathophysiology; priority journal; protein expression; protein synthesis; signal transduction; vascular disease; vascular leakage; Animals; Capillary Permeability; Chorionic Gonadotropin; Cytokine Receptor gp130; Disease Models, Animal; Endothelial Cells; Female; Follicle Stimulating Hormone; Follicular Fluid; Granulosa Cells; Hormones; Humans; Interleukin-6; Mice; Mice, Inbred ICR; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Protein Kinase C; Receptors, Interleukin-6; Reproductive Control Agents; Risk Factors; Signal Transduction; Vascular Endothelial Growth Factor A |
顯示於: | 醫學系 |
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