Interleukin-22 promotes proliferation and reverses LPS-induced apoptosis and steroidogenesis attenuation in human ovarian granulosa cells: implications for polycystic ovary syndrome pathogenesis

Abstract

Objective

Interleukin 22 (IL-22) plays a role in inflammatory diseases. However, whether IL-22 affects the function of ovarian granulosa cells (GCs) and its relationship with Polycystic Ovary Syndrome (PCOS)remains unclear.

Methods

We investigated the level of IL-22 in human follicular fluid using ELISA. The expression and localization of the IL-22 receptor 1 (IL-22R1) in GCs were investigated by RT-PCR and immunofluorescence staining, respectively. The proliferation of KGN cells (human GCs line) was assessed by CCK-8 assay and EdU assay after treatment with recombinant human IL-22 (rhIL-22) and lipopolysaccharide (LPS). Apoptosis was assessed using flow cytometry. Apoptotic proteins and steroidogenic genes were detected by western blotting.

Results

ELISA's results showed that compared with the control group, PCOS patients showed lower expression of IL-22 in follicular fluid. Immunofluorescence showed that IL-22R1 is expressed and localized in human granulosa cell membranes. IL-22 promoted cell proliferation and reversed LPS-induced inhibition of cell proliferation. IL-22 alone did not affect apoptotic or steroidogenic protein expression, however, it reversed LPS-induced apoptosis via downregulation of Bcl-2, upregulation of Bax and cleaved caspase-3, and restoration of LPS-downregulated StAR, CYP11A1, and CYP19A1 expression. Western blotting confirmed that IL-22 activated the JAK2/STAT3 signaling.

Conclusion

IL-22 promotes cell proliferation, inhibits apoptosis, and regulates KGN cell steroidogenesis confronted with LPS, and decreased IL-22 may be involved in the development of PCOS.

Graphical abstract

Keywords:

• Polycystic ovary syndrome
•  Interleukin 22
•  Inflammation
•  Apoptosis
•  Steroidogenesis

Acknowledgment

The authors are grateful to everyone who contributed to this study.

Ethical approval

The First Affiliated Hospital of Chongqing Medical University’s Ethics Committee approved all procedures used in studies involving individuals.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability

Data availability on request from the corresponding author.

Additional information

Funding

This work was supported by the Natural Science Foundation of Chongqing China (NO. (cstc2021jcyj-msxmX0506), Program for Youth Innovation in Future Medicine, Chongqing Medical University (NO. W0130) and Open project of Chongqing Key Laboratory of Human Embryo Engineering (NO.2020KFKT006).