Interleukin-4 activates the PI3K/AKT signaling to promote apoptosis and inhibit the proliferation of granulosa cells

• Published in: Experimental cell research 2022-03, Vol.412 (1), p.113002-113002, Article 113002
• Main Authors: Han, Ying, Yao, Ruqiang, Yang, Zexin, Li, Shuang, Meng, Wenjia, Zhang, Yinfeng, Zhang, Yunshan, Luo, Haining
• Format: Article
• Language: English
• Subjects: Adult; Apoptosis; Apoptosis - drug effects; Case-Control Studies; Cell Proliferation - drug effects; Cells, Cultured; Cellular Microenvironment; Chromones - pharmacology; Female; Follicular Fluid - metabolism; Granulosa cells; Granulosa Cells - drug effects; Granulosa Cells - metabolism; Granulosa Cells - pathology; Humans; IL-4; Inflammation; Interleukin-1beta - metabolism; Interleukin-4 - metabolism; Interleukin-4 - pharmacology; Interleukin-6 - metabolism; Morpholines - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; PI3K/Akt signaling; Primary Ovarian Insufficiency - metabolism; Primary Ovarian Insufficiency - pathology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2021.113002

The inflammatory microenvironment has been demonstrated to play a role in folliculogenesis, ovulation and premature ovarian failure (POF), as well as infertility. In this study, we aimed to explore the role of inflammation in modulating growth and apoptosis in granulosa cells (GCs), the main components of ovarian follicles. ELISA was used to analyze the levels of inflammatory factors (IL-1β, IL-4, IL-6 and IL-10) in follicular fluid samples and GCs derived from POF patients and healthy normal individuals. CCK-8, flow cytometry and TUNEL assays were used to assess the effect of IL-4 on GC growth and apoptosis. Western blotting was used to examine the effect of IL-4 on the activation of PI3K/Akt, Erk1/2 and Jnk signaling. The results showed that IL-4, IL-1β and IL-6 levels were increased in follicular fluid samples and GCs derived from POF patients compared with those from healthy individuals. GC growth was weakened when cells were treated with IL-4, while apoptosis was increased. In addition, IL-4 increased the level of p-Akt/Akt in GCs. In addition, LY294002, an inhibitor of PI3K, abolished the effect of IL-4 by inhibiting GC growth and promoting apoptosis. In summary, this study demonstrated that IL-4 levels were increased in POF samples and that IL-4 could inhibit GC growth and induce GC apoptosis by activating PI3K/Akt signaling.