Chronic stress regulates endometrial autophagy through IL-6/JAK2/BECN1 signaling pathway

Stress adversely affects various aspects of the female reproductive process, including follicle development, maturation, ovulation, luteal activity, and embryo implantation. Restraint stress reduces the number of implantated embryos. The precise mechanisms by which stress affects embryo implantation are not fully understood. In this study, a mouse model of restraint stress was used to investigate the effects of stress on uterine receptivity and the underlying mechanisms. Mice were randomly divided into three groups. The groups were the Control group, Stress group, and Ab-IL-6 treatment group. Mice in the Stress and Ab-IL-6 treatment groups underwent restraint stress in perforated 50 ml centrifuge tubes for 4 hours daily over 7 consecutive days. Results indicated that the number of implanted blastocysts and total litter size in the stress group were significantly lower than those in the control group. These findings indicate that restraint stress leads to high IL-6 expression in the endometrium. This increased expression may affect the endometrium's receptivity, resulting in a decreased number of implanted blastocysts. Furthermore, we demonstrated that IL-6 regulated autophagy through the IL-6/JAK2/BECN1 pathway in Ishikawa cells and mouse endometrial epithelial cells, and treatment with an IL-6 antibody significantly mitigated the adverse effects of stress-induced blastocyst implantation. Our findings demonstrated that restraint stress had a negative influence on endometrial receptivity via the IL-6/JAK2/BECN1 pathway. This effect led to a reduction in the number of implanted embryos. Consequently, inhibiting IL-6 expression may represent a potential therapeutic strategy for preventing stress-induced implantation failure.