IL-6 Promotes FSH-Induced VEGF Expression Through JAK/STAT3 Signaling Pathway in Bovine Granulosa Cells

Abstract

Background/Aims: Vascular endothelial growth factor (VEGF) has been demonstrated to play a pivotal role in the regulation of angiogenesis in ovarian follicular development, particularly during the preovulatory period. Although numerous studies have shown that interleukin-6 (IL-6) is one of the major inducing factors that regulate the expression of VEGF in non-ovarian cells, whether it involved in regulating the expression of VEGF in normal ovarian granulosa cells is still unknown. The aim of this study was to elucidate the mechanisms underlying the effect of IL-6 on FSH-induced VEGF expression in bovine granulosa cells derived from large follicles. Methods: VEGF mRNA expression in granulosa cells after IL-6 with/without inhibitors treatment was analyzed by RT-qPCR. Phosphorylation levels of ERK1/2 and STAT3 proteins induced by IL-6 were analyzed by western blotting. The protein levels produced by granulosa cells were detected by ELISA. Results: High concentration of IL-6 (10ng/ml) can significantly up-regulate FSH-induced VEGF gene and protein expression levels in granulosa cells, and also promote the VEGF upstream regulators HIF-1α and COX2 mRNA expression. VEGF expression levels were significantly decreased after specifically blocking HIF-1α and COX2 by using inhibitors. The up-regulation effect of IL-6 on FSH-induced VEGF expression in granulosa cells mainly through activating the JAK/STAT3 signaling pathway, which can be impaired by JAK inhibitors. Conclusion: IL-6 can promote FSH-induced VEGF expression in granulosa cells, which is mainly achieved by increasing the expression of HIF-1α and COX2.This promoting effect is mediated by activating the JAK/STAT3 pathway. Moreover, there may be a synergistic relationship between FSH and IL-6 in the regulation of VEGF expression.

Hormonal regulation of vascular endothelial growth factor A (VEGFA) gene expression in granulosa and theca cells of cattle1

“…FSH and LH stimulate VEGFA mRNA abundance in mice GC (Rico et al, 2014) and bovine LG-follicle GC (Klipper et al, 2010;Yang et al, 2017), whereas in the present study, FSH had an inhibitory effect on VEGFA mRNA abundance in SM-follicle GC and no effect in LG-follicle GC. Also in the present study, LH had no effect on VEGFA mRNA in LG-follicle GC but stimulated VEGFA mRNA in LG-follicle TC.…”

Allicin Inhibits Proliferation and Invasion in Vitro and in Vivo via SHP-1-Mediated STAT3 Signaling in Cholangiocarcinoma

“…In our study, we focused on how allicin inhibits CCA cell proliferation and invasion through STAT3 signaling. STAT3 is a key transcription factor involved in inflammation [44], angiogenesis [45], migration, and proliferation [46]. It is considered as an oncogene due to its tumor-promoting effect.…”

The Role of Growth Hormone on Ovarian Functioning and Ovarian Angiogenesis

“…Among the factors regulating VEGF family expression in humans GH plays a pivotal role, either directly or by inducing the expression of other proangiogenic factors, such as the Insulin-like growth factors (IGF-1 and IGF-2), FGF-2, epidermal growth factor (EGF), among others; moreover, GH is able to interact with receptors for Prolactin (PRL), which also is able to induce proangiogenic effects [for review, see (106)]. At this point, it is important to note that the pituitary secretion of GH is strongly potentiated by sex steroids, mainly E2, which in its free form (fE2) directly reaches the central nervous system (CNS), or is formed at this level from the hypothalamic aromatization of testosterone (9).…”