{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T07:56:15Z","timestamp":1767858975741,"version":"3.49.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["rep.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Inflammation plays a central role in the terminal process of human labour and delivery, including myometrial contractions. RAF1 proto-oncogene serine\/threonine-protein kinase (RAF1) can activate ERK (official gene symbol MAPK1) and\/or nuclear factor-kappa B (NF-\u03baB) to regulate genes involved in inflammation. There are, however, no studies on the role of RAF1 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour and pro-inflammatory cytokines interleukin 1 beta (IL1B) and tumour necrosis factor (TNF) alpha on RAF1 protein expression in myometrium and ii) siRNA knockdown of RAF1 on pro-inflammatory and pro-labour mediators in human myometrial primary cells. Term labour was associated with an increase in RAF1 protein expression. Furthermore, RAF1 protein expression was increased in myometrial cells treated with IL1B and TNF, two likely factors contributing to preterm birth. Knockdown of RAF1 by siRNA in primary myometrial cells significantly decreased IL1B- and TNF-induced IL1A, IL1B, IL6, (C-X-C motif) ligand 8 (CXCL8)and chemokine (C-C motif) ligand 2 (CCL2) mRNA abundance and IL6, IL8 and CCL2; prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA levels and prostaglandin PGF2\u03b1 release; and NF-\u03baB activation. Furthermore, RAF1 knockdown was associated with decreased activation of ERK in the presence of IL1B but not TNF. Concordantly, the ERK inhibitor U0126 significantly decreased IL1B-induced IL6, CXCL8, CCL2 and PTGS2 mRNA abundance; IL6, CXCL8, CCL2 and PGF2\u03b1 release; and NF-\u03baB activation. In conclusion, IL1B induces the expression and secretion of pro-labour mediators through the RAF1\u2013MAPK1\u2013NF-\u03baB signalling pathway. TNF, on the other hand, regulates pro-labour mediators through the RAF1\u2013NF-\u03baB signalling pathway via an MAPK1-independent mechanism.<\/jats:p>","DOI":"10.1530\/rep-15-0607","type":"journal-article","created":{"date-parts":[[2016,2,23]],"date-time":"2016-02-23T22:43:50Z","timestamp":1456267430000},"page":"411-420","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":10,"title":["RAF1 is increased in labouring myometrium and modulates inflammation-induced pro-labour mediators"],"prefix":"10.1093","volume":"151","author":[{"given":"Martha","family":"Lappas","sequence":"first","affiliation":[{"name":"Mercy Perinatal Research Centre Mercy Hospital for Women, Heidelberg, Victoria, Australia 2 Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4\/163 Studley Road, Heidelberg 3084, Victoria, Australia"},{"name":"Obstetrics Mercy Hospital for Women, Heidelberg, Victoria, Australia 2 Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4\/163 Studley Road, Heidelberg 3084, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,4,1]]},"reference":[{"key":"2026010712432641200_bib1","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1002\/j.1460-2075.1994.tb06424.x","article-title":"Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1","volume":"13","author":"Alessi","year":"1994","journal-title":"EMBO Journal"},{"key":"2026010712432641200_bib2","doi-asserted-by":"crossref","first-page":"6362","DOI":"10.1093\/emboj\/18.22.6362","article-title":"The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression","volume":"18","author":"Barradas","year":"1999","journal-title":"EMBO Journal"},{"key":"2026010712432641200_bib3","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1469-7793.1999.00399.x","article-title":"Induction of cyclooxygenase-2 expression in human myometrial smooth muscle cells by interleukin-1\u03b2: involvement of p38 mitogen-activated protein kinase","volume":"520","author":"Bartlett","year":"1999","journal-title":"Journal of Physiology"},{"key":"2026010712432641200_bib4","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1073\/pnas.080583397","article-title":"Raf induces NF-\u03ba B by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation","volume":"97","author":"Baumann","year":"2000","journal-title":"PNAS"},{"issue":"Suppl 1","key":"2026010712432641200_bib5","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1742-4755-10-S1-S2","article-title":"Born too soon: the global epidemiology of 15 million preterm births","volume":"10","author":"Blencowe","year":"2013","journal-title":"Reproductive Health"},{"key":"2026010712432641200_bib6","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1053\/plac.2001.0782","article-title":"Cytokines of the placenta and extra-placental membranes: roles and regulation during human pregnancy and parturition","volume":"23","author":"Bowen","year":"2002","journal-title":"Placenta"},{"key":"2026010712432641200_bib7","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1128\/jvi.71.1.398-404.1997","article-title":"Adenovirus infection stimulates the Raf\/MAPK signaling pathway and induces interleukin-8 expression","volume":"71","author":"Bruder","year":"1997","journal-title":"Journal of Virology"},{"key":"2026010712432641200_bib8","doi-asserted-by":"crossref","first-page":"7783","DOI":"10.1073\/pnas.141224398","article-title":"Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism","volume":"98","author":"Chen","year":"2001","journal-title":"PNAS"},{"key":"2026010712432641200_bib9","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jri.2008.04.002","article-title":"Inflammatory processes in preterm and term parturition","volume":"79","author":"Christiaens","year":"2008","journal-title":"Journal of Reproductive Immunology"},{"key":"2026010712432641200_bib10","doi-asserted-by":"crossref","first-page":"29485","DOI":"10.1074\/jbc.M801269200","article-title":"TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NF-\u03ba B","volume":"283","author":"Edelblum","year":"2008","journal-title":"Journal of Biological Chemistry"},{"key":"2026010712432641200_bib11","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1053\/j.gastro.2008.04.025","article-title":"Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-\u03ba B","volume":"135","author":"Edelblum","year":"2008","journal-title":"Gastroenterology"},{"key":"2026010712432641200_bib12","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1083\/jcb.200409162","article-title":"Raf-1 regulates Rho signaling and cell migration","volume":"168","author":"Ehrenreiter","year":"2005","journal-title":"Journal of Cell Biology"},{"key":"2026010712432641200_bib13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.ccr.2009.06.008","article-title":"Raf-1 addiction in Ras-induced skin carcinogenesis","volume":"16","author":"Ehrenreiter","year":"2009","journal-title":"Cancer Cell"},{"key":"2026010712432641200_bib14","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1034\/j.1600-0897.2001.d01-11.x","article-title":"IL-1\u03b2 and IL-8 in human fetal membranes: changes with gestational age, labor, and culture conditions","volume":"46","author":"Elliott","year":"2001","journal-title":"American Journal of Reproductive Immunology"},{"key":"2026010712432641200_bib15","first-page":"3468","article-title":"Expression of cyclooxygenase-2 and prostanoid receptors by human myometrium","volume":"85","author":"Erkinheimo","year":"2000","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026010712432641200_bib16","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/BF03403535","article-title":"Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the ras\/raf-1\/MEK\/MAPK pathway","volume":"1","author":"Geppert","year":"1994","journal-title":"Molecular Medicine"},{"key":"2026010712432641200_bib17","doi-asserted-by":"crossref","first-page":"21281","DOI":"10.1074\/jbc.272.34.21281","article-title":"The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of I\u03baB\u03b1 and stimulates its degradation in vitro","volume":"272","author":"Ghoda","year":"1997","journal-title":"Journal of Biological Chemistry"},{"key":"2026010712432641200_bib18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1006\/smim.2000.0210","article-title":"The I \u03ba B kinase (IKK) and NF-\u03ba B: key elements of proinflammatory signalling","volume":"12","author":"Karin","year":"2000","journal-title":"Seminars in Immunology"},{"key":"2026010712432641200_bib19","doi-asserted-by":"crossref","first-page":"S33","DOI":"10.1053\/plac.2002.0948","article-title":"Cytokines, prostaglandins and parturition \u2013 a review","volume":"24","author":"Keelan","year":"2003","journal-title":"Placenta"},{"key":"2026010712432641200_bib20","doi-asserted-by":"crossref","first-page":"504952","DOI":"10.1155\/2012\/504952","article-title":"NF\u03baB and AP-1 drive human myometrial IL8 expression","volume":"2012","author":"Khanjani","year":"2012","journal-title":"Mediators of Inflammation"},{"key":"2026010712432641200_bib21","doi-asserted-by":"crossref","first-page":"24313","DOI":"10.1074\/jbc.271.40.24313","article-title":"Sounding the alarm: protein kinase cascades activated by stress and inflammation","volume":"271","author":"Kyriakis","year":"1996","journal-title":"Journal of Biological Chemistry"},{"key":"2026010712432641200_bib22","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1530\/REP-14-0597","article-title":"KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium","volume":"149","author":"Lappas","year":"2015","journal-title":"Reproduction"},{"key":"2026010712432641200_bib23","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.plefa.2003.04.001","article-title":"Phospholipase A2 isozymes in pregnancy and parturition","volume":"70","author":"Lappas","year":"2004","journal-title":"Prostaglandins, Leukotrienes, and Essential Fatty Acids"},{"key":"2026010712432641200_bib24","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.placenta.2006.05.011","article-title":"The role and regulation of the nuclear factor \u03ba B signalling pathway in human labour","volume":"28","author":"Lappas","year":"2007","journal-title":"Placenta"},{"key":"2026010712432641200_bib25","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1095\/biolreprod67.2.668","article-title":"Nuclear factor \u03ba B regulation of proinflammatory cytokines in human gestational tissues in vitro","volume":"67","author":"Lappas","year":"2002","journal-title":"Biological Reproduction"},{"key":"2026010712432641200_bib26","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1210\/jc.2002-021677","article-title":"N-acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-\u03baB deoxyribonucleic acid-binding activity in human fetal membranes in vitro","volume":"88","author":"Lappas","year":"2003","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026010712432641200_bib27","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.placenta.2007.02.009","article-title":"Mitogen-activated protein kinase proteins regulate LPS-stimulated release of pro-inflammatory cytokines and prostaglandins from human gestational tissues","volume":"28","author":"Lappas","year":"2007","journal-title":"Placenta"},{"key":"2026010712432641200_bib28","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.placenta.2011.09.011","article-title":"MAPK and AP-1 proteins are increased in term pre-labour fetal membranes overlying the cervix: regulation of enzymes involved in the degradation of fetal membranes","volume":"32","author":"Lappas","year":"2011","journal-title":"Placenta"},{"key":"2026010712432641200_bib29","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1095\/biolreprod.113.108126","article-title":"A novel role for FOXO3 in human labor: increased expression in laboring myometrium, and regulation of proinflammatory and prolabor mediators in pregnant human myometrial cells","volume":"88","author":"Lim","year":"2013","journal-title":"Biological Reproduction"},{"key":"2026010712432641200_bib30","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1177\/1933719113503406","article-title":"TREM-1 expression is increased in human placentas from severe early-onset preeclamptic pregnancies where it may be involved in syncytialization","volume":"21","author":"Lim","year":"2014","journal-title":"Reproductive Sciences"},{"key":"2026010712432641200_bib31","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1095\/biolreprod.115.134726","article-title":"The transcription factor interferon regulatory factor-1 (IRF1) plays a key role in the terminal effector pathways of human preterm labor","volume":"94","author":"Lim","year":"2016","journal-title":"Biology of Reproduction"},{"key":"2026010712432641200_bib32","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1530\/rep.1.00197","article-title":"The role of nuclear factor \u03ba B in human labour","volume":"130","author":"Lindstrom","year":"2005","journal-title":"Reproduction"},{"key":"2026010712432641200_bib33","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/aji.12366","article-title":"The stress-responsive heme oxygenase (HO)-1 isoenzyme is increased in labouring myometrium where it regulates contraction-associated proteins","volume":"74","author":"Liong","year":"2015","journal-title":"American Journal of Reproductive Immunology"},{"key":"2026010712432641200_bib34","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1471-4159.2010.06747.x","article-title":"Inhibition of extracellular signal-regulated kinases 1\/2 provides neuroprotection in spinal cord ischemia\/reperfusion injury in rats: relationship with the nuclear factor-\u03baB-regulated anti-apoptotic mechanisms","volume":"114","author":"Lu","year":"2010","journal-title":"Journal of Neurochemistry"},{"key":"2026010712432641200_bib35","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.4161\/cc.8.8.8147","article-title":"How ERK1\/2 activation controls cell proliferation and cell death is subcellular localization the answer?","volume":"8","author":"Mebratu","year":"2009","journal-title":"Cell Cycle"},{"key":"2026010712432641200_bib36","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1038\/sj.onc.1210414","article-title":"The ERK1\/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition","volume":"26","author":"Meloche","year":"2007","journal-title":"Oncogene"},{"key":"2026010712432641200_bib37","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1073\/pnas.95.7.3537","article-title":"Differential regulation of I\u03baB kinase \u03b1 and \u03b2 by two upstream kinases, NF-\u03baB-inducing kinase and mitogen-activated protein kinase\/ERK kinase kinase-1","volume":"95","author":"Nakano","year":"1998","journal-title":"PNAS"},{"key":"2026010712432641200_bib38","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/molehr\/gag001","article-title":"Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term","volume":"9","author":"Osman","year":"2003","journal-title":"Molecular Human Reproduction"},{"key":"2026010712432641200_bib39","doi-asserted-by":"crossref","first-page":"e21542","DOI":"10.1371\/journal.pone.0021542","article-title":"Phasic phosphorylation of caldesmon and ERK 1\/2 during contractions in human myometrium","volume":"6","author":"Paul","year":"2011","journal-title":"PLoS ONE"},{"key":"2026010712432641200_bib40","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/j.8755-8920.2000.430304.x","article-title":"Interleukin-1 stimulates human uterine prostaglandin production through induction of cyclooxygenase-2 expression","volume":"43","author":"Rauk","year":"2000","journal-title":"American Journal of Reproductive Immunology"},{"key":"2026010712432641200_bib41","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1093\/molehr\/6.1.96","article-title":"Up-regulation of matrix metalloproteinase-9 in human myometrium during labour: a cytokine-mediated process in uterine smooth muscle cells","volume":"6","author":"Roh","year":"2000","journal-title":"Molecular Human Reproduction"},{"key":"2026010712432641200_bib42","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/S0002-9378(12)80035-4","article-title":"The natural interleukin-1 receptor antagonist prevents interleukin-1-induced preterm delivery in mice","volume":"167","author":"Romero","year":"1992","journal-title":"American Journal of Obstetrics and Gynaecology"},{"key":"2026010712432641200_bib43","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/0002-9378(91)90450-6","article-title":"Systemic administration of interleukin-1 induces preterm parturition in mice","volume":"165","author":"Romero","year":"1991","journal-title":"American Journal of Obstetrics and Gynaecology"},{"key":"2026010712432641200_bib44","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.phrs.2012.04.005","article-title":"ERK1\/2 MAP kinases: structure, function, and regulation","volume":"66","author":"Roskoski","year":"2012","journal-title":"Pharmacology Research"},{"key":"2026010712432641200_bib45","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1016\/j.ajog.2006.06.072","article-title":"Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model","volume":"195","author":"Sadowsky","year":"2006","journal-title":"American Journal of Obstetrics and Gynaecology"},{"key":"2026010712432641200_bib46","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1177\/1933719112446084","article-title":"Physiologic uterine inflammation and labor onset: integration of endocrine and mechanical signals","volume":"20","author":"Shynlova","year":"2013","journal-title":"Reproductive Sciences"},{"key":"2026010712432641200_bib47","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1530\/REP-07-0461","article-title":"Pro-labour myometrial gene expression: are preterm labour and term labour the same?","volume":"135","author":"Tattersall","year":"2008","journal-title":"Reproduction"},{"key":"2026010712432641200_bib48","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1093\/humrep\/14.1.229","article-title":"Leukocytes infiltrate the myometrium during human parturition: further evidence that labour is an inflammatory process","volume":"14","author":"Thomson","year":"1999","journal-title":"Human Reproduction"},{"key":"2026010712432641200_bib49","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1095\/biolreprod.102.011403","article-title":"Interleukin-1\u03b2 induces calcium transients and enhances basal and store operated calcium entry in human myometrial smooth muscle","volume":"68","author":"Tribe","year":"2003","journal-title":"Biological Reproduction"}],"container-title":["Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rep.bioscientifica.com\/view\/journals\/rep\/151\/4\/411.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/151\/4\/411\/64133065\/411.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/151\/4\/411\/64133065\/411.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T17:44:06Z","timestamp":1767807846000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/reproduction\/article\/151\/4\/411\/8236141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,1]]},"references-count":49,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2016,4,1]]}},"URL":"https:\/\/doi.org\/10.1530\/rep-15-0607","relation":{},"ISSN":["1470-1626","1741-7899"],"issn-type":[{"value":"1470-1626","type":"print"},{"value":"1741-7899","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,4,1]]},"published":{"date-parts":[[2016,4,1]]}}}