{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T12:07:53Z","timestamp":1768910873439,"version":"3.49.0"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T00:00:00Z","timestamp":1667952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chang Gung Memorial Hospital, Taiwan","award":["CMRP37133"],"award-info":[{"award-number":["CMRP37133"]}]},{"name":"Chang Gung Memorial Hospital, Taiwan","award":["CMRPG3E0771"],"award-info":[{"award-number":["CMRPG3E0771"]}]},{"name":"Chang Gung Memorial Hospital, Taiwan","award":["CMRPG3K0781\/3K0782"],"award-info":[{"award-number":["CMRPG3K0781\/3K0782"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Adenomyosis is a uterine pathology characterized by a deep invasion of endometrial glands and stroma, disrupting the endometrial\u2013myometrial interface (EMI). Interleukin-18 (IL-18) system is a dominant cytokine involved in the menstrual cycle of human endometrium. IL-18 may play a defensive role against maternal immune response in the uterine cavity. The present study was designed to determine IL-18-mediated immune response at the level of EMI. We uncovered that mRNA of IL-18 system, including IL-18, IL-18 receptor (IL-18R), and its antagonist, IL-18 binding protein (IL-18BP), expressed in eutopic, ectopic endometrium, and corresponding myometrium in patients with adenomyosis. IL-18 system was demonstrated in paired tissue samples by immunochemistry and immunofluorescence study. According to RT-PCR with CT value quantification and 2\u2212\u2206\u2206Ct method, a significant down-regulation of IL-18BP in corresponding myometrium in comparison to eutopic endometrium (p &lt; 0.05) indicates that the IL-18 system acts as a local immune modulator at the level of EMI and regulating cytokine networks in the pathogenesis of adenomyosis. Furthermore, an increased IL-18 antagonist to agonist ratio was noted in ectopic endometrium compared with corresponding myometrium. We suggest that altered IL-18 system expression contributes to immunological dysfunction and junctional zone disturbance in women with adenomyosis.<\/jats:p>","DOI":"10.3390\/cimb44110376","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T02:49:38Z","timestamp":1667962178000},"page":"5550-5561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Altered Expression of Interleukin-18 System mRNA at the Level of Endometrial Myometrial Interface in Women with Adenomyosis"],"prefix":"10.3390","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-6962","authenticated-orcid":false,"given":"Liang-Hsuan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"She-Hung","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Cosmetic Science, Providence University, No. 200, Sec. 7, Taiwan Boulevard, Shalu Dist., Taichung 43301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chin-Jung","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsien-Ming","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong-Yuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan"},{"name":"Department of Obstetrics and Gynecology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.bpobgyn.2018.06.002","article-title":"Endometriosis and infertility: Insights into the causal link and management strategies","volume":"51","author":"Tomassetti","year":"2018","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1210\/er.2018-00242","article-title":"Endometriosis","volume":"40","author":"Bulun","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/s41574-019-0245-z","article-title":"Rethinking mechanisms, diagnosis and management of endometriosis","volume":"15","author":"Chapron","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1093\/humupd\/dmaa038","article-title":"Immunological changes associated with adenomyosis: A systematic review","volume":"27","author":"Bourdon","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1093\/humupd\/dmab017","article-title":"Adenomyosis pathogenesis: Insights from next-generation sequencing","volume":"27","author":"Bulun","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.bpobgyn.2006.01.010","article-title":"Adenomyosis: The pathophysiology of an oestrogen-dependent disease","volume":"20","author":"Kitawaki","year":"2006","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102228","DOI":"10.1016\/j.jogoh.2021.102228","article-title":"Adenomyosis: An update regarding its diagnosis and clinical features","volume":"50","author":"Bourdon","year":"2021","journal-title":"J. Gynecol. Obstet. Hum. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1080\/09513590.2021.1878131","article-title":"Adenomyosis and infertility: The role of the junctional zone","volume":"37","author":"Barbanti","year":"2021","journal-title":"Gynecol. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.fertnstert.2020.12.010","article-title":"Endometrial causes of recurrent pregnancy losses: Endometriosis, adenomyosis, and chronic endometritis","volume":"115","author":"Pirtea","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_10","first-page":"301","article-title":"The endometrium in adenomyosis","volume":"8","author":"Benagiano","year":"2012","journal-title":"Women\u2019s Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/0002-9378(61)90082-5","article-title":"Relationship of adenomyosis uteri to endometrial hyperplasia and endometrial carcinoma","volume":"82","author":"Marcus","year":"1961","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.fertnstert.2012.06.044","article-title":"The pathophysiology of uterine adenomyosis: An update","volume":"98","author":"Benagiano","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1097\/00006254-200006000-00025","article-title":"Endometrial-myometrial interface: Relationship to adenomyosis and changes in pregnancy","volume":"55","author":"Uduwela","year":"2000","journal-title":"Obstet. Gynecol. Surv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0015-0282(00)01630-7","article-title":"Immunobiology of endometriosis","volume":"75","author":"Lebovic","year":"2001","journal-title":"Fertil. Steril."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0889-8545(02)00052-9","article-title":"Pathogenesis of endometriosis","volume":"30","author":"Seli","year":"2003","journal-title":"Obstet. Gynecol. Clin. N. Am."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.bpobgyn.2004.01.004","article-title":"Genetics of endometriosis: Heritability and candidate genes","volume":"18","author":"Bischoff","year":"2004","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1016\/j.fertnstert.2008.02.164","article-title":"Expression of interleukin-10 in patients with adenomyosis","volume":"91","author":"Wang","year":"2009","journal-title":"Fertil. Steril."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.fertnstert.2013.04.008","article-title":"Comparative serum proteomic analysis of adenomyosis using the isobaric tags for relative and absolute quantitation technique","volume":"100","author":"Xiaoyu","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1093\/molehr\/7.7.649","article-title":"Evidence for the expression of interleukin (IL)-18, IL-18 receptor and IL-18 binding protein in the human endometrium","volume":"7","author":"Yoshino","year":"2001","journal-title":"Mol. Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.fertnstert.2006.02.122","article-title":"Interleukin-18 system messenger RNA and protein expression in human endometrium during the menstrual cycle","volume":"86","author":"Huang","year":"2006","journal-title":"Fertil. Steril."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0952-7915(01)00306-5","article-title":"IL-1 and IL-18 receptors, and their extended family","volume":"14","author":"Sims","year":"2002","journal-title":"Curr. Opin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/meth.1999.0837","article-title":"Interleukin-18","volume":"19","author":"Dinarello","year":"1999","journal-title":"Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0952-7915(99)00051-5","article-title":"The role of IL-18 in innate immunity","volume":"12","author":"Akira","year":"2000","journal-title":"Curr. Opin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/378088a0","article-title":"Cloning of a new cytokine that induces IFN-gamma production by T cells","volume":"378","author":"Okamura","year":"1995","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1146\/annurev.immunol.19.1.423","article-title":"Interleukin-18 regulates both Th1 and Th2 responses","volume":"19","author":"Nakanishi","year":"2001","journal-title":"Ann. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1089\/jir.2012.0029","article-title":"Interleukin-18 in pulmonary inflammatory diseases","volume":"32","author":"Kawayama","year":"2012","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/386619a0","article-title":"Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production","volume":"386","author":"Ghayur","year":"1997","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4103\/0970-2113.63609","article-title":"Role played by Th2 type cytokines in IgE mediated allergy and asthma","volume":"27","author":"Deo","year":"2010","journal-title":"Lung India"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1097\/00054725-199911000-00009","article-title":"Th1\/Th2 cells","volume":"5","author":"Romagnani","year":"1999","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/nsb993","article-title":"The structure and binding mode of interleukin-18","volume":"10","author":"Kato","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S1074-7613(00)80013-8","article-title":"Interleukin-18 binding protein: A novel modulator of the Th1 cytokine response","volume":"10","author":"Novick","year":"1999","journal-title":"Immunity"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S0015-0282(03)01122-1","article-title":"Altered expression of interleukin-18 in the peritoneal fluid of women with endometriosis","volume":"80","author":"Arici","year":"2003","journal-title":"Fertil. Steril."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/humrep\/deh108","article-title":"Role of IL-18 in pathogenesis of endometriosis","volume":"19","author":"Oku","year":"2004","journal-title":"Hum. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.fertnstert.2003.09.074","article-title":"Decreased levels of interleukin-18 in peritoneal fluid but not in serum of patients with endometriosis","volume":"81","author":"Zhang","year":"2004","journal-title":"Fertil. Steril."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.jri.2006.03.003","article-title":"Altered expression of interleukin-18 in the ectopic and eutopic endometrium of women with endometriosis","volume":"72","author":"Luo","year":"2006","journal-title":"J. Reprod. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.fertnstert.2009.01.132","article-title":"Eutopic endometrial interleukin-18 system mRNA and protein expression at the level of endometrial-myometrial interface in adenomyosis patients","volume":"94","author":"Huang","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_37","first-page":"1721","article-title":"Cytokine-mediated regulation of 92-kilodalton type IV collagenase, tissue inhibitor or metalloproteinase-1 (TIMP-1), and TIMP-3 messenger ribonucleic acid expression in human endometrial stromal cells","volume":"83","author":"Huang","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_39","first-page":"1","article-title":"Aberrant FOXP3 gene expression in eutopic and ectopic endometrium of infertile women with endometriosis","volume":"8","author":"Cavalcanti","year":"2015","journal-title":"Int. Arch. Med."},{"key":"ref_40","first-page":"549","article-title":"Localization of interleukin-1 type I receptor and interleukin-1 beta in human endometrium throughout the menstrual cycle","volume":"77","author":"Simon","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1093\/oxfordjournals.humrep.a136326","article-title":"Immunohistochemical localization, identification and regulation of the interleukin-1 receptor antagonist in the human endometrium","volume":"10","author":"Simon","year":"1995","journal-title":"Hum. Reprod."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1210\/edrv-12-3-272","article-title":"Human endometrium: An active site of cytokine production and action","volume":"12","author":"Tabibzadeh","year":"1991","journal-title":"Endocr. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1530\/rep.0.1230217","article-title":"Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis","volume":"123","author":"Gazvani","year":"2002","journal-title":"Reproduction"},{"key":"ref_44","first-page":"1387","article-title":"Interleukin (IL)-1beta regulation of IL-1beta and IL-1 receptor antagonist expression in cultured human endometrial stromal cells","volume":"86","author":"Huang","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_45","first-page":"333","article-title":"Peritoneal fluid environment in endometriosis. Clinicopathological implications","volume":"55","author":"Bedaiwy","year":"2003","journal-title":"Minerva Ginecol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/j.1600-0897.2012.01147.x","article-title":"Imbalance in cytokines from interleukin-1 family-role in pathogenesis of endometriosis","volume":"68","author":"Sikora","year":"2012","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S1359-6101(00)00015-0","article-title":"Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu","volume":"12","author":"Nakanishi","year":"2001","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1084\/jem.188.8.1485","article-title":"Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells","volume":"188","author":"Xu","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(04)17403-5","article-title":"Endometriosis","volume":"364","author":"Giudice","year":"2004","journal-title":"Lancet"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.fertnstert.2021.11.024","article-title":"Endometrial cytokines in patients with and without endometriosis evaluated for infertility","volume":"117","author":"Jorgensen","year":"2022","journal-title":"Fertil. Steril."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1177\/1933719115597761","article-title":"Cytokine Profiling in the Eutopic Endometrium of Adenomyosis During the Implantation Window After Ovarian Stimulation","volume":"23","author":"Zhihong","year":"2016","journal-title":"Reprod. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.fertnstert.2007.11.060","article-title":"Interleukin-12 but not interleukin-18 is associated with severe endometriosis","volume":"91","author":"Fairbanks","year":"2009","journal-title":"Fertil. Steril."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1590\/S0100-879X2009001100007","article-title":"Peritoneal and serum interleukin-18 levels are not increased in women with minimum or mild endometriosis","volume":"42","author":"Glitz","year":"2009","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/0002-9378(72)90781-8","article-title":"The elusive adenomyosis of the uterus\u2014Revisited","volume":"112","author":"Bird","year":"1972","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/S0140-6736(95)91387-4","article-title":"Uterine junctional zone: Function and disease","volume":"346","author":"Brosens","year":"1995","journal-title":"Lancet"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2015.10.034","article-title":"Estrogen Receptor beta Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis","volume":"163","author":"Han","year":"2015","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Park, C., Jeong, J.W., Lee, D.S., Yim, M.J., Lee, J.M., Han, M.H., Kim, S., Kim, H.S., Kim, G.Y., and Park, E.K. (2018). Sargassum serratifolium Extract Attenuates Interleukin-1beta-Induced Oxidative Stress and Inflammatory Response in Chondrocytes by Suppressing the Activation of NF-kappaB, p38 MAPK, and PI3K\/Akt. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082308"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1002\/cbin.11592","article-title":"E3 ubiquitin ligase TRIM24 deficiency promotes NLRP3\/caspase-1\/IL-1beta-mediated pyroptosis in endometriosis","volume":"45","author":"Hang","year":"2021","journal-title":"Cell Biol. Int."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Di Nicuolo, F., Castellani, R., De Cicco Nardone, A., Barbaro, G., Paciullo, C., Pontecorvi, A., Scambia, G., and Di Simone, N. (2021). Alpha-Lipoic Acid Plays a Role in Endometriosis: New Evidence on Inflammasome-Mediated Interleukin Production, Cellular Adhesion and Invasion. Molecules, 26.","DOI":"10.3390\/molecules26020288"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/44\/11\/376\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:12:57Z","timestamp":1760145177000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/44\/11\/376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,9]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["cimb44110376"],"URL":"https:\/\/doi.org\/10.3390\/cimb44110376","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,9]]}}}