Endoplasmic reticulum stress response and the regulation of endometrial interferon-beta production

Objective: To gain an understanding of the potential role of endoplasmic reticulum (ER) stress in the endometrial compartment during early pregnancy, a highly understudied area. Design: This study examined the regulation of interferon-,6 (IFN,6) in response to ER stress in human decidualized and nondecidualized endometrial cells (human endometrial stromal cells [HESCs]) in vitro. In vivo, we examined ER stress and the IFN,6 levels locally in the mouse endometrium before and after implantation at embryonic day (E)1, E3, and E6. Setting: The study was performed in a reproductive sciences laboratory for Human Growth and Development. Patient(s): None. Intervention(s): None. Main Outcome Measure(s): Quantitative polymerase chain reaction, Western blotting, and immunohistochemical analysis allowed us to test the action of endogenous ER stress activation in the endometrial compartment likely triggered by implantation and its ability to increase the endometrial IFN,6 levels. Result(s): In vitro, we observed a significant difference in the IFN,6 levels in HESCs, in response to ER stress activation, where decidualized HESCs exhibited a threefold increase in the IFN,6 levels compared with nondecidualized HESCs. Apoptotic caspase-3 activation was also isolated to the decidualized cells as a result of ER stress-dependent suppression of nuclear factor-kappa beta-regulated antiapoptotic factors, XIAP and MCL-1. In vivo, mouse endometrial IFN,6 was present in F4/80-positive macrophages at all time points examined. After implantation (E6), the mouse luminal epithelial cells robustly coexpressed both IFN,6 and the ER stress marker immunoglobulin heavy chain binding protein (BiP). Conclusion(s): These analyses demonstrate that both in vivo and in vitro, differentiated and decidualized endometrial cells undergoing ER stress have the capacity to produce increased IFN,6 levels; therefore, ER stress activation in the endometrial compartment may play a vital role in promoting successful implantation events. (c) 2023 by American Society for Reproductive Medicine.