Cross-Talk Between FSH and Endoplasmic Reticulum Stress: A Mutually Suppressive Relationship.
Suboptimal cellular conditions result in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and trigger ER stress. In this study, we investigated the effects of follicle stimulating hormone (FSH) on ER stress in granulosa cells (GCs) obtained from 3-week-old female C57BL6 mice 24 or 48 hours after intraperitoneal injection of 5 IU pregnant mare's serum gonadotropin (PMSG), and in primary mouse GCs in culture treated with FSH (10-100 mIU/mL) for 24 or 48 hours. Moreover, mouse GCs in culture were treated with tunicamycin (Tm) or thapsigargin (Tp), which induce ER stress by inhibiting N-glycosylation of ER proteins and ER calcium adenosine triphosphatase, respectively, and their response to FSH was evaluated. We found that FSH attenuated ER stress in mouse GCs in vivo and in vitro; messenger RNA levels of ER stress-associated genes Xbp1s, Atf6, Chop, and Casp12 were decreased upon exposure to FSH/PMSG. Activating transcription factor 4 protein levels also demonstrated consistent decrease following FSH stimulation. Both Tm and Tp treatments inhibited FSH response, ER stress-induced cells did not show any change in estradiol levels in response to FSH, whereas in untreated GCs, estradiol production increased 3-fold after incubation with FSH for 60 hours. Furthermore, ER stress-induced cells failed to demonstrate aromatase (Cyp19a1) expression upon exposure to FSH. Importantly, under high-ER stress conditions FSH stimulation was unable to downregulate the expression of ER stress-associated genes. Our findings suggest that FSH decreases ER stress in GCs under physiologic conditions. However, under conditions that cause a significant increase in ER stress, FSH response is attenuated.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Elnur
E
Babayev
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA Biogen Idec, Cambridge, MA, USA.
Maria D
MD
Lalioti
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Federico
F
Favero
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA emre.seli@yale.edu.
Emre
E
Seli
D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006736:Horses; D051379:Mice; D008810:Mice, Inbred C57BL; D010053:Ovary / Q000378:metabolism*; D010062:Ovulation Induction / Q000379:methods; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology*
D005640:Follicle Stimulating Hormone
FSH; endoplasmic reticulum stress; granulosa cell; unfolded protein response