The role of IL-6 trans-signaling in vascular leakage: implications for ovarian hyperstimulation syndrome in a murine model.
BACKGROUND
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.


METHODS
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.
Department of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
Lin-Hung
LH
Wei
Chia-Hung
CH
Chou
Min-Wei
MW
Chen
Stefan
S
Rose-John
Min-Liang
ML
Kuo
Shee-Uan
SU
Chen
Yu-Shih
YS
Yang
D000818:Animals; D002199:Capillary Permeability / Q000276:immunology; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D015571:Follicular Fluid / Q000276:immunology / Q000378:metabolism; D006107:Granulosa Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D016471:Ovarian Hyperstimulation Syndrome / Q000453:epidemiology / Q000276:immunology* / Q000378:metabolism*; D010062:Ovulation Induction / Q000379:methods; D011493:Protein Kinase C / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000378:metabolism; D012102:Reproductive Control Agents / Q000494:pharmacology; D012307:Risk Factors; D015398:Signal Transduction / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D006063:Chorionic Gonadotropin; D006728:Hormones; C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D012102:Reproductive Control Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C577686:interleukin-6, mouse; C467480:vascular endothelial growth factor A, mouse; D050822:Cytokine Receptor gp130; D005640:Follicle Stimulating Hormone; D011493:Protein Kinase C