Interleukin-33 stimulates stress in the endoplasmic reticulum of the human myometrium via an influx of calcium during initiation of labor

BackgroundInflammation is currently recognized as one of the major causes of premature delivery. As a member of the IL-1{beta} family, interleukin-33 (IL-33) has been shown to be involved in a variety of pregnancy-related diseases. This study aims to investigate the potential function of IL-33 in uterine smooth muscle cells during labor. MethodsSamples of myometrium from term pregnant ([≥]37 weeks gestation) women were frozen or cells were isolated and cultured. Immunohistochemistry and western blotting were used to identify the distribution of IL-33. Cultured cells were incubated with LPS to mimic inflammation as well as 48C to block endoplasmic reticulum (ER) stress and BAPTA-AM, a calcium chelator. ResultsSimilar with onset of labor, LPS could reduce the expression of nuclear IL-33 in a time-limited manner and induced ER stress. Meanwhile, Knockdown of IL-33 increased LPS-induced calcium concentration, ER stress and phosphorylation of NF-{kappa}B and p38. In addition, siRNA IL-33 further simulates LPS enhanced COX-2 expression via NF-{kappa}B 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. However, after IL-33 was knockdown, the stimulating effect of LPS on calcium was enhanced. 48C also inhibited the expression of COX-2 markedly. The expression of calcium channels on the membrane and intracellular free calcium ion were both increased accompanied by phosphorylated NF-{kappa}B and p38. ConclusionsThese data suggest that IL-33 may be involved in initiation of labor by leading to stress of the ER via an influx of calcium ions in human uterine smooth muscle cells. FundingThis study was supported by grants from the National Natural Science Foundation of China (Nos. 81300507).