TY - JOUR TI - Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor AU - Chen, Li AU - Song, Zhenzhen AU - Cao, Xiaowan AU - Fan, Mingsong AU - Zhou, Yan AU - Zhang, Guoying A2 - Huang, Christopher L-H A2 - Zaidi, Mone VL - 11 PY - 2022 DA - 2022/08/23 SP - e75072 C1 - eLife 2022;11:e75072 DO - 10.7554/eLife.75072 UR - https://doi.org/10.7554/eLife.75072 AB - Background:. Inflammation is currently recognized as one of the major causes of premature delivery. As a member of the interleukin-1β (IL-1β) family, interleukin-33 (IL-33) has been shown to be involved in normal pregnancy as well as a variety of pregnancy-related disorder. This study aims to investigate the potential function of IL-33 in uterine smooth muscle cells during labor. Methods:. Myometrium samples from term pregnant (≥37 weeks gestation) women were either frozen or cells were isolated and cultured. Immunohistochemistry and western blotting were used to assess the distribution of IL-33. Cultured cells were incubated with lipopolysaccharide (LPS) to mimic inflammation as well as in the presence of 4μ8C (IRE1 inhibitor III) to block endoplasmic reticulum (ER) stress and BAPTA-AM, a calcium chelator. Results:. LPS reduced the expression of nuclear IL-33 in a time-limited manner and induced ER stress. However, knockdown of IL-33 increased LPS-induced calcium concentration, ER stress and phosphorylation of nuclear factor kappa-B (NF-κB), and P38 mitogen-activated protein kinase (P38 MAPK). In addition, siRNA IL-33 further stimulates LPS enhanced cyclooxygenase-2 (COX-2) expression via NF-κB and p38 pathways. IL-33 expression was decreased in the nucleus with the onset of labor. LPS-induced ER stress and increased expression of the labor-associated gene, COX-2, as well as IL-6 and IL-8 in cultured myometrial cells. IL-33 also increased COX-2 expression, but after it was knocked down, the stimulating effect of LPS on calcium was enhanced. 4μ8C also inhibited the expression of COX-2 markedly. The expression of calcium channels on the membrane and intracellular free calcium ion were both increased which was accompanied by phosphorylated NF-κB and p38. Conclusions:. These data suggest that IL-33 may be involved in the initiation of labor by leading to stress of the ER via an influx of calcium ions in human uterine smooth muscle cells. Funding:. This study was supported by grants from the National Natural Science Foundation of China (No. 81300507). KW - preterm labor KW - myometrium KW - interleukin-33 KW - inflammation KW - calcium channels KW - stress JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -