{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:36:20Z","timestamp":1785418580978,"version":"3.56.0"},"reference-count":37,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81300507"],"award-info":[{"award-number":["81300507"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,8,14]]},"abstract":"<jats:sec id=\"abs1\">\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Inflammation is currently recognized as one of the major causes of premature delivery. As a member of the interleukin-1\u03b2 (IL-1\u03b2) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Myometrium samples from term pregnant (\u226537 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 4\u03bc8C (IRE1 inhibitor III) to block endoplasmic reticulum (ER) stress and BAPTA-AM, a calcium chelator.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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-\u03baB), and P38 mitogen-activated protein kinase (P38 MAPK). In addition, siRNA IL-33 further stimulates LPS enhanced cyclooxygenase-2 (COX-2) expression via NF-\u03baB 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. 4\u03bc8C 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-\u03baB and p38.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>This study was supported by grants from the National Natural Science Foundation of China (No. 81300507).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.75072","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T06:15:16Z","timestamp":1660544116000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.75072","source":"Crossref","is-referenced-by-count":15,"title":["Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6673-2963","authenticated-orcid":true,"given":"Li","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059gcgy73","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Song","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059gcgy73","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowan","family":"Cao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059gcgy73","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingsong","family":"Fan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059gcgy73","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059gcgy73","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoying","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059gcgy73","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.4049\/jimmunol.1003080","article-title":"The dual function cytokine IL-33 interacts with the transcription factor NF-\u03bab to dampen NF-\u03bab-stimulated gene transcription","volume":"187","author":"Ali","year":"2011","journal-title":"Journal of Immunology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1111\/febs.14608","article-title":"Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications","volume":"286","author":"Almanza","year":"2019","journal-title":"The FEBS Journal"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/ng.2830","article-title":"A genome-wide association study identifies CDHR3 as A susceptibility locus for early childhood asthma with severe exacerbations","volume":"46","author":"B\u00f8nnelykke","year":"2014","journal-title":"Nature Genetics"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1073\/pnas.0606854104","article-title":"IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo","volume":"104","author":"Carriere","year":"2007","journal-title":"PNAS"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1111\/imr.12619","article-title":"Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family","volume":"281","author":"Cayrol","year":"2018","journal-title":"Immunological Reviews"},{"key":"bib6","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9787239","article-title":"Decreased IL-33 production contributes to trophoblast cell dysfunction in pregnancies with preeclampsia","volume":"2018","author":"Chen","year":"2018","journal-title":"Mediators of Inflammation"},{"key":"bib7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau6499","article-title":"IRE1\u03b1-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain","volume":"365","author":"Chopra","year":"2019","journal-title":"Science"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1111\/imr.12552","article-title":"IL-33: biological properties, functions, and roles in airway disease","volume":"278","author":"Drake","year":"2017","journal-title":"Immunological Reviews"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"3734","DOI":"10.4049\/jimmunol.1300490","article-title":"Macrophage-derived IL-33 is a critical factor for placental growth","volume":"191","author":"Fock","year":"2013","journal-title":"Journal of Immunology"},{"key":"bib10","doi-asserted-by":"publisher","DOI":"10.1038\/srep34255","article-title":"Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells","volume":"6","author":"Gautier","year":"2016","journal-title":"Scientific Reports"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.jri.2018.06.029","article-title":"Inflammation induced preterm labor and birth","volume":"129","author":"Gilman-Sachs","year":"2018","journal-title":"Journal of Reproductive Immunology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S0140-6736(08)60074-4","article-title":"Epidemiology and causes of preterm birth","volume":"371","author":"Goldenberg","year":"2008","journal-title":"Lancet"},{"key":"bib13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00475","article-title":"The ST2\/IL-33 axis in immune cells during inflammatory diseases","volume":"8","author":"Griesenauer","year":"2017","journal-title":"Frontiers in Immunology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.cytogfr.2017.09.005","article-title":"Pathophysiology of IL-33 and IL-17 in allergic disorders","volume":"38","author":"Gupta","year":"2017","journal-title":"Cytokine & Growth Factor Reviews"},{"key":"bib15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18040792","article-title":"Endoplasmic reticulum stress and homeostasis in reproductive physiology and pathology","volume":"18","author":"Guzel","year":"2017","journal-title":"International Journal of Molecular Sciences"},{"key":"bib16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2018.08.021","article-title":"Amnion epithelial cell-derived exosomes induce inflammatory changes in uterine cells","volume":"219","author":"Hadley","year":"2018","journal-title":"American Journal of Obstetrics and Gynecology"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"245","DOI":"10.2147\/JIR.S248382","article-title":"Antibiotics, inflammation, and preterm labor: A missed conclusion","volume":"13","author":"Hantoushzadeh","year":"2020","journal-title":"Journal of Inflammation Research"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1093\/molehr\/gat094","article-title":"IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of CCL2\/CCR2 via NF-\u03bab and ERK1\/2 signaling","volume":"20","author":"Hu","year":"2014","journal-title":"Molecular Human Reproduction"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.jri.2015.01.004","article-title":"Decidual stromal cell-derived IL-33 contributes to th2 bias and inhibits decidual NK cell cytotoxicity through NF-\u03bab signaling in human early pregnancy","volume":"109","author":"Hu","year":"2015","journal-title":"Journal of Reproductive Immunology"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/nm.4244","article-title":"Interleukin-33-induced expression of PIBF1 by decidual B cells protects against preterm labor","volume":"23","author":"Huang","year":"2017","journal-title":"Nature Medicine"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1111\/all.12593","article-title":"IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk","volume":"70","author":"Kaur","year":"2015","journal-title":"Allergy"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1093\/biolre\/ioab211","article-title":"Blocking the bkca channel induces NF-\u03baB nuclear translocation by increasing nuclear calcium concentration\u2020","volume":"106","author":"Kent","year":"2022","journal-title":"Biology of Reproduction"},{"key":"bib23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00566","article-title":"Advances in the prevention of infection-related preterm birth","volume":"6","author":"Lamont","year":"2015","journal-title":"Frontiers in Immunology"},{"key":"bib24","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.114.120741","article-title":"Endoplasmic reticulum stress is increased after spontaneous labor in human fetal membranes and myometrium where it regulates the expression of prolabor mediators","volume":"91","author":"Liong","year":"2014","journal-title":"Biology of Reproduction"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/ni.3370","article-title":"Interleukin 33 is a guardian of barriers and a local alarmin","volume":"17","author":"Martin","year":"2016","journal-title":"Nature Immunology"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1146\/annurev-pathol-012513-104649","article-title":"The role of endoplasmic reticulum stress in human pathology","volume":"10","author":"Oakes","year":"2015","journal-title":"Annual Review of Pathology"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.coi.2018.04.006","article-title":"Involvement of ion channels in allergy","volume":"52","author":"Pelletier","year":"2018","journal-title":"Current Opinion in Immunology"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1126\/science.1251816","article-title":"Preterm labor: one syndrome, many causes","volume":"345","author":"Romero","year":"2014","journal-title":"Science"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/nrm2199","article-title":"Signal integration in the endoplasmic reticulum unfolded protein response","volume":"8","author":"Ron","year":"2007","journal-title":"Nature Reviews. Molecular Cell Biology"},{"key":"bib30","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd3865","article-title":"Exosomal delivery of NF-\u03bab inhibitor delays LPS-induced preterm birth and modulates fetal immune cell profile in mouse models","volume":"7","author":"Sheller-Miller","year":"2021","journal-title":"Science Advances"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12836","article-title":"IL-33\/ST2 axis affects the polarization and efferocytosis of decidual macrophages in early pregnancy","volume":"79","author":"Sheng","year":"2018","journal-title":"American Journal of Reproductive Immunology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.placenta.2020.02.005","article-title":"Myometrial activation: novel concepts underlying labor","volume":"92","author":"Shynlova","year":"2020","journal-title":"Placenta"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.placenta.2014.05.013","article-title":"Extracellular ATP decreases trophoblast invasion, spiral artery remodeling and immune cells in the mesometrial triangle in pregnant rats","volume":"35","author":"Spaans","year":"2014","journal-title":"Placenta"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"4448","DOI":"10.1073\/pnas.1000803107","article-title":"IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin","volume":"107","author":"Theoharides","year":"2010","journal-title":"PNAS"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1007\/978-981-13-5895-1_10","article-title":"The myometrium: from excitation to contractions and labour","volume":"1124","author":"Wray","year":"2019","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1016\/j.bbrc.2017.09.153","article-title":"Interleukin-33 attenuates doxorubicin-induced cardiomyocyte apoptosis through suppression of ASK1\/JNK signaling pathway","volume":"493","author":"Yao","year":"2017","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib37","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqz028","article-title":"The endoplasmic reticulum and calcium homeostasis in pancreatic beta cells","volume":"161","author":"Zhang","year":"2020","journal-title":"Endocrinology"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/75072\/elife-75072-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/75072\/elife-75072-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/75072","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:12:02Z","timestamp":1697058722000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/75072"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,23]]},"references-count":37,"alternative-id":["10.7554\/eLife.75072"],"URL":"https:\/\/doi.org\/10.7554\/elife.75072","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.11.05.21265965","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.75072.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.75072.sa0","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.75072.sa1","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,23]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"e75072"}}