{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T23:05:19Z","timestamp":1789599919792,"version":"build-2803163510"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["8180061745, 81771613"],"award-info":[{"award-number":["8180061745, 81771613"]}],"id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2016YFC1000407"],"award-info":[{"award-number":["2016YFC1000407"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Preterm labor (PTL) is a multifactorial syndrome that results in birth prior to 37 weeks of gestation. However, the specific molecular mechanisms underlying this condition have yet to be elucidated. Previous research demonstrated that the abnormal expression of IL-27, and its receptors, played a role in the pathophysiology of preterm labor. In the present study, we established a Lipopolysaccharide (LPS)-stimulated, infection-induced, preterm mouse model based on wild-type C57BL\/6 mice and WSX-1<jats:sup>-\/-<\/jats:sup>C57BL\/6 mice. WSX-1 knockdown led to a significant delay in birth by 11.32 \u00b1 2.157h. In addition, compared with wild-type C57B\/6 mice, the expression levels of <jats:italic>IFN-\u03b3, IL-1\u03b2, IL-6, TNF-\u03b1, and CXCL10<\/jats:italic>, in the fetal membrane and myometrium of WSX-1<jats:sup>-\/-<\/jats:sup>mice were significantly lower, particularly in the myometrium. We also confirmed similar pro-inflammatory effects arising from IL-27 in human amniotic cell line (WISH) and human myometrial smooth muscle cell line (HMSMC). Once stimulated by LPS, the pro-inflammatory action exhibited a synergistic effect and appeared to be time-dependent. Finally, we demonstrated that LY3214996, an inhibitor of the ERK pathway, significantly inhibited the pro-inflammatory effect mediated by IL-27. Overall, our data confirmed that the inflammatory effect mediated by the IL-27\/IFN-r\/ERK axis is involved in preterm labor. Our findings, therefore, provide an enhancement in our etiological understanding of the mechanisms underlying PTL.<\/jats:p>","DOI":"10.3389\/fimmu.2021.709229","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T19:32:15Z","timestamp":1633894335000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["IL-27 Mediates Pro-Inflammatory Effects via the ERK Signaling Pathway During Preterm Labor"],"prefix":"10.3389","volume":"12","author":[{"given":"Dongni","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Ran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanlin","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/14767058.2017.1323860","article-title":"Preterm Labor and Birth Management: Recommendations From the European Association of Perinatal Medicine","volume":"30","author":"Di Renzo","year":"2017","journal-title":"J Maternal-Fetal Neonatal Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1016\/S0140-6736(16)32170-5","article-title":"The Lancet. The Unfinished Agenda of Preterm Births","volume":"388","year":"2016","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4755-10-S1-S2","article-title":"The Born Too Soon Preterm Birth Action Group (See Acknowledgement for Full List). Born Too Soon: The Global Epidemiology of 15 Million Preterm Births","volume":"10","author":"Blencowe","year":"2013","journal-title":"Reprod Health"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2013-1131","article-title":"Late Preterm Infants: Near Term But Still in a Critical Developmental Time Period","volume":"132","author":"Kugelman","year":"2013","journal-title":"Pediatrics"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61577-8","article-title":"Long-Term Neurodevelopmental Outcomes After Intrauterine and Neonatal Insults: A Systematic Review","volume":"379","author":"Mwaniki","year":"2012","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0043-6","article-title":"The Complex Aetiology of Cerebral Palsy","volume":"14","author":"Korzeniewski","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1251816","article-title":"Preterm Labor: One Syndrome, Many Causes","volume":"345","author":"Romero","year":"2014","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009871","article-title":"Prevention of Preterm Birth: Harnessing Science to Address the Global Epidemic","volume":"6","author":"Rubens","year":"2014","journal-title":"Sci Trans Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"021","DOI":"10.1055\/s-2006-956773","article-title":"The Role of Inflammation and Infection in Preterm Birth","volume":"25","author":"Romero","year":"2007","journal-title":"Semin Reprod Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-016-0632-4","article-title":"Modeling Hormonal and Inflammatory Contributions to Preterm and Term Labor Using Uterine Temporal Transcriptomics","volume":"14","author":"Migale","year":"2016","journal-title":"BMC Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1016\/j.cell.2018.06.045","article-title":"Stereotypic Immune System Development in Newborn Children","volume":"174","author":"Olin","year":"2018","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.placenta.2016.05.013","article-title":"Human Fetal Membranes at Term: Dead Tissue or Signalers of Parturition","volume":"44","author":"Menon","year":"2016","journal-title":"Placenta"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(99)70711-8","article-title":"Immunoendocrinology of Preterm Labor: The Link Between Corticotropin-Releasing Hormone and Inflammation","volume":"180","author":"Dudley","year":"1999","journal-title":"Am J Obstet Gynecol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3275\/8816","article-title":"Activin A Is Stimulated by Tumor Necrosis Factor-Alpha and Modulates Collagen Gene Expression in Human Amniotic Cells","volume":"36","author":"Abe","year":"2013","journal-title":"J Endocrinol Invest"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2014.46","article-title":"Immune Cells in Term and Preterm Labor","volume":"11","author":"Gomez-Lopez","year":"2014","journal-title":"Cell Mol Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1189\/jlb.3MR0615-272RR","article-title":"Inflammation and Preterm Birth","volume":"99","author":"Cappelletti","year":"2016","journal-title":"J Leukocyte Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100217","article-title":"Functional Screening of TLRs in Human Amniotic Epithelial Cells","volume":"187","author":"Gillaux","year":"2011","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(99)70301-7","article-title":"Association of Oligohydramnios in Women With Preterm Premature Rupture of Membranes With an Inflammatory Response in Fetal, Amniotic, and Maternal Compartments","volume":"181","author":"Yoon","year":"1999","journal-title":"Am J Obstet Gynecol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1080\/jmf.11.1.18.25","article-title":"Funisitis and Chorionic Vasculitis: The Histological Counterpart of the Fetal Inflammatory Response Syndrome","volume":"11","author":"Pacora","year":"2002","journal-title":"J Matern Fetal Neonatal Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2007.06.004","article-title":"Expression of Interleukin-27 by Human Trophoblast Cells","volume":"28","author":"Coulomb-L\u2019Hermin\u00e9","year":"2007","journal-title":"Placenta"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1177\/1933719118799206","article-title":"Interleukin-27 Inhibits Trophoblast Cell Invasion and Migration by Affecting the Epithelial\u2013Mesenchymal Transition in Preeclampsia","volume":"26","author":"Ge","year":"2019","journal-title":"Reprod Sci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e12706","DOI":"10.1111\/aji.12706","article-title":"The Cross Talk Between Cervical Carcinoma Cells and Vascular Endothelial Cells Mediated by IL-27 Restrains Angiogenesis","volume":"78","author":"Zhang","year":"2017","journal-title":"Am J Reprod Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.cyto.2009.08.013","article-title":"Cytokine Expression in Placenta-Derived Mesenchymal Stem Cells in Patients With Pre-Eclampsia and Normal Pregnancies","volume":"49","author":"Hwang","year":"2010","journal-title":"Cytokine"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2017.06.031","article-title":"IL-27 Induces a Pro-Inflammatory Response in Human Fetal Membranes Mediating Preterm Birth","volume":"50","author":"Yin","year":"2017","journal-title":"Int Immunopharmacol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.1945894","article-title":"Identification of the Correlations Between Interleukin-27 (IL-27) and Immune-Inflammatory Imbalance in Preterm Birth","volume":"12","author":"Ran","year":"2021","journal-title":"Bioengineered"},{"key":"B26","doi-asserted-by":"publisher","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":"J Reprod Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.bpobgyn.2018.01.022","article-title":"The Biological Basis and Prevention of Preterm Birth","volume":"52","author":"Di Renzo","year":"2018","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3996","DOI":"10.1210\/en.2010-0063","article-title":"Interleukin-6 Is an Essential Determinant of On-Time Parturition in the Mouse","volume":"151","author":"Robertson","year":"2010","journal-title":"Endocrinology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1911579117","article-title":"Dysregulation of TLR9 in Neonates Leads to Fatal Inflammatory Disease Driven by IFN-\u03b3","volume":"117","author":"Stanbery","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12298","article-title":"Interleukin-18 and Interferon Gamma Levels in Preeclampsia: A Systematic Review and Meta-Analysis","volume":"72","author":"Yang","year":"2014","journal-title":"Am J Reprod Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/7154524","article-title":"Characterization of Natural Killer Cells and Cytokines in Maternal Placenta and Fetus of Diabetic Mothers","volume":"2016","author":"Hara C de","year":"2016","journal-title":"J Immunol Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12555","article-title":"EPHB4, a Down Stream Target of IFN-\u03b3\/STAT1 Signal Pathway, Regulates Endothelial Activation Possibly Contributing to the Development of Preeclampsia","volume":"76","author":"Liu","year":"2016","journal-title":"Am J Reprod Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gan018","article-title":"IFN- -Mediated Extravillous Trophoblast Outgrowth Inhibition in First Trimester Explant Culture: A Role for Insulin-Like Growth Factors","volume":"14","author":"Hu","year":"2008","journal-title":"Mol Hum Reprod"},{"key":"B34","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/s0165-0378(96)00990-4","article-title":"Interleukin-6, Interferon-Y, Interleukin-8, and Granulocyte-Macrophage Colony Stimulating Factor Levels in Human Amniotic Fluid at Term","volume":"32","author":"OlBh\u2019","year":"1996","journal-title":"J Reprod Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1080\/00016340701515423","article-title":"Mid-Pregnancy Maternal Plasma Levels of Interleukin 2, 6, and 12, Tumor Necrosis Factor-Alpha, Interferon-Gamma, and Granulocyte-Macrophage Colony-Stimulating Factor and Spontaneous Preterm Delivery","volume":"86","author":"Curry","year":"2007","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000182592.76702.E8","article-title":"Circulating Interferon-Gamma and White Matter Brain Damage in Preterm Infants","volume":"58","author":"Hansen-Pupp","year":"2005","journal-title":"Pediatr Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2008-1222","article-title":"Differential Patterns of 27 Cord Blood Immune Biomarkers Across Gestational Age","volume":"123","author":"Matoba","year":"2009","journal-title":"PEDIATRICS"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2004.00162.x","article-title":"IFN-Gamma-Mediated Inhibition of COX-2 Expression in the Placenta From Term and Preterm Labor Pregnancies","volume":"51","author":"Hanna","year":"2004","journal-title":"Am J Reprod Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms11010222","article-title":"ERK in Learning and Memory: A Review of Recent Research","volume":"11","author":"Peng","year":"2010","journal-title":"IJMS"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(03)00300-5","article-title":"The IL-27r (WSX-1) Is Required to Suppress T Cell Hyperactivity During Infection","volume":"19","author":"Villarino","year":"2003","journal-title":"Immunity"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.10464","article-title":"Biology of IL-27 and Its Role in the Host Immunity Against Mycobacterium Tuberculosis","volume":"11","author":"Abdalla","year":"2015","journal-title":"Int J Biol Sci"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(01)00206-0","article-title":"WSX-1 Is Required for the Initiation of Th1 Responses and Resistance to L. Major Infection","volume":"15","author":"Yoshida","year":"2001","journal-title":"Immunity"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/926875","article-title":"IL-27 Activates Human Trophoblasts to Express IP-10 and IL-6: Implications in the Immunopathophysiology of Preeclampsia","volume":"2014","author":"Yin","year":"2014","journal-title":"Mediators Inflammation"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/s0959-437x(01)00260-x","article-title":"Anchorage-Dependent ERK Signaling \u2013 Mechanisms and Consequences","volume":"12","author":"Howe","year":"","journal-title":"Curr Opin Genet Dev"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3109\/10799893.2015.1030412","article-title":"Signaling Pathway of MAPK\/ERK in Cell Proliferation, Differentiation, Migration, Senescence and Apoptosis","volume":"35","author":"Sun","year":"2015","journal-title":"J Receptors Signal Transduct"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e0152838","DOI":"10.1371\/journal.pone.0152838","article-title":"Hydrogen Sulfide Delays LPS-Induced Preterm Birth in Mice via Anti-Inflammatory Pathways","volume":"11","author":"Liu","year":"2016","journal-title":"PloS One"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00042.2004","article-title":"Role of ERK1\/2 in Uterine Contractility and Preterm Labor in Rats","volume":"287","author":"Li","year":"2004","journal-title":"Am J Physiol-Regulat Integr Comp Physiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-1390","article-title":"The Mitogen-Activated Protein Kinase Dependent Expression of Prostaglandin H Synthase-2 and Interleukin-8 Messenger Ribonucleic Acid by Myometrial Cells: The Differential Effect of Stretch and Interleukin-1\u03b2","volume":"90","author":"Sooranna","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1042\/CS20180368","article-title":"Increase in Soluble Protein Oligomers Triggers the Innate Immune System Promoting Inflammation and Vascular Dysfunction in the Pathogenesis of Sepsis","volume":"132","author":"Komic","year":"2018","journal-title":"Clin Sci"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23606","article-title":"Inhibition of MAPK\/ERK Pathway Promotes Oligodendrocytes Generation and Recovery of Demyelinating Diseases","volume":"67","author":"Suo","year":"2019","journal-title":"Glia"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242889","article-title":"ERK Differentially Regulates Th17- and Treg-Cell Development and Contributes to the Pathogenesis of Colitis: Cellular Immune Response","volume":"43","author":"Liu","year":"2013","journal-title":"Eur J Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02847","article-title":"Sonic Hedgehog Signaling Pathway Mediates Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via MAPK\/ERK Signaling Pathway","volume":"9","author":"Liu","year":"2018","journal-title":"Front Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gav001","article-title":"Activation of Decidual Invariant Natural Killer T Cells Promotes Lipopolysaccharide-Induced Preterm Birth","volume":"21","author":"Li","year":"2015","journal-title":"MHR: Basic Sci Reprod Med"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-19-0183","article-title":"ERK Inhibitor LY3214996 Targets ERK Pathway\u2013Driven Cancers: A Therapeutic Approach Toward Precision Medicine","volume":"19","author":"Bhagwat","year":"2020","journal-title":"Mol Cancer Ther"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00553","article-title":"Cigarette Smoke Induction of Interleukin-27\/WSX-1 Regulates the Differentiation of Th1 and Th17 Cells in a Smoking Mouse Model of Emphysema","volume":"7","author":"Qiu","year":"2016","journal-title":"Front Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2012.313","article-title":"IL-27 Activates Th1-Mediated Responses in Imiquimod-Induced Psoriasis-Like Skin Lesions","volume":"133","author":"Shibata","year":"2013","journal-title":"J Invest Dermatol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-013-2341-0","article-title":"Interleukin-27 as a Potential Therapeutic Target for Rheumatoid Arthritis: Has the Time Come","volume":"32","author":"Gong","year":"2013","journal-title":"Clin Rheumatol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106538","article-title":"IL-27 and Autoimmune Rheumatologic Diseases: The Good, the Bad, and the Ugly","volume":"84","author":"Shahi","year":"2020","journal-title":"Int Immunopharmacol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.709229\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T19:32:20Z","timestamp":1633894340000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.709229\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,8]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2021.709229"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.709229","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,8]]},"article-number":"709229"}}