{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T02:02:51Z","timestamp":1787968971774,"version":"build-2784847793"},"reference-count":33,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20H03133"],"award-info":[{"award-number":["20H03133"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K10694"],"award-info":[{"award-number":["15K10694"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alpha-1 antitrypsin (A1AT) is a glycoprotein that has been shown to protect tissues from proteolytic damage under various inflammatory conditions. Several studies show that A1AT may be associated with pre-eclampsia. However, the role of A1AT expression in placental physiology is not fully understood. In the present study, we aim to characterize the expression and function of placental A1AT. A1AT knockdown is found to reduce the expression of the serine protease HTRA1 in a trophoblast cell line. In addition, A1AT overexpression (A1AT-OE) increases the expression of HTRA1, IL6, CXCL8, and several markers of endoplasmic reticulum (ER) stress. Treatment with tunicamycin or thapsigargin, which induces ER stress, increases HTRA1 expression. Furthermore, immunohistochemistry reveals that HTRA1 is expressed in trophoblasts and the endometrial decidual cells of human placentas. An invasion assay shows that A1AT and HTRA1 stimulate cell invasion, but treatment with the ER stress inhibitors reduces the expression of HTRA1 and ER stress markers and prevents cell invasion in A1AT-OE trophoblasts. These results suggest that endogenous A1AT regulates inflammatory cytokine expression and HTRA1-induced trophoblast invasion via the induction of ER stress. It is concluded that an imbalance in the functional link between A1AT and ER stress at the maternal\u2013fetal interface might cause abnormal placental development.<\/jats:p>","DOI":"10.3390\/ijms22073683","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T10:44:01Z","timestamp":1617273841000},"page":"3683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Alpha-1 Antitrypsin-Induced Endoplasmic Reticulum Stress Promotes Invasion by Extravillous Trophoblasts"],"prefix":"10.3390","volume":"22","author":[{"given":"Kanoko","family":"Yoshida","sequence":"first","affiliation":[{"name":"Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9120-0475","authenticated-orcid":false,"given":"Kazuya","family":"Kusama","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako","family":"Ohmaru-Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoko","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3351-895X","authenticated-orcid":false,"given":"Kazuhiro","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,1]]},"reference":[{"key":"ref_1","first-page":"1809","article-title":"Human cytotrophoblast differentiation\/invasion is abnormal in pre-eclampsia","volume":"151","author":"Lim","year":"1997","journal-title":"Am. J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1007\/s11906-011-0214-y","article-title":"Mechanisms and management of hypertension in pregnant women","volume":"13","author":"Brown","year":"2011","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"827","DOI":"10.2174\/156652412801318755","article-title":"Alpha 1 anti-trypsin: One protein, many functions","volume":"12","author":"Hunt","year":"2012","journal-title":"Curr. Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1177\/1933719115570901","article-title":"Possible Role of alpha1-Antitrypsin in Endometriosis-Like Grafts From a Mouse Model of Endometriosis","volume":"22","author":"Tamura","year":"2015","journal-title":"Reprod. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Starodubtseva, N., Nizyaeva, N., Baev, O., Bugrova, A., Gapaeva, M., Muminova, K., Kononikhin, A., Frankevich, V., Nikolaev, E., and Sukhikh, G. (2020). SERPINA1 Peptides in Urine as A Potential Marker of Preeclampsia Severity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030914"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15007","DOI":"10.1073\/pnas.1309648110","article-title":"Anti-inflammatory and immunomodulatory properties of \u03b11-antitrypsin without inhibition of elastase","volume":"110","author":"Jonigk","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Frochaux, V., Hildebrand, D., Talke, A., Linscheid, M.W., and Schl\u00fcter, H. (2014). Alpha-1-antitrypsin: A novel human high temperature requirement protease A1 (HTRA1) substrate in human placental tissue. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109483"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1093\/humrep\/der019","article-title":"Decidual HtrA3 negatively regulates trophoblast invasion during human placentation","volume":"26","author":"Singh","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1038\/s41598-019-39565-9","article-title":"HtrA4 may play a major role in inhibiting endothelial repair in pregnancy complication preeclampsia","volume":"9","author":"Wang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/boc.201800023","article-title":"Measuring the effects of alpha1 -antitrypsin polymerisation on the structure and biophysical properties of the endoplasmic reticulum","volume":"110","author":"Chambers","year":"2018","journal-title":"Biol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.cell.2016.12.004","article-title":"Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer","volume":"168","author":"Bettigole","year":"2017","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.virusres.2014.09.016","article-title":"Coronavirus-induced ER stress response and its involvement in regulation of coronavirus-host interactions","volume":"194","author":"Fung","year":"2014","journal-title":"Virus Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ando, Y., Kuroda, A., Kusama, K., Matsutani, T., Matsuda, A., and Tamura, K. (2021). Impact of serine protease inhibitor alpha1-antitrypsin on expression of endoplasmic reticulum stress-induced proinflammatory factors in adipocytes. Biochem. Biophys. Rep., 26.","DOI":"10.1016\/j.bbrep.2021.100967"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.ajpath.2018.10.015","article-title":"Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine-Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy","volume":"189","author":"Lee","year":"2019","journal-title":"Am. J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22958","DOI":"10.1074\/jbc.M114.576744","article-title":"Functional antagonism between high temperature requirement protein A (HtrA) family members regulates trophoblast invasion","volume":"289","author":"Chen","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_16","first-page":"977","article-title":"HtrA protease family as therapeutic targets","volume":"19","author":"Koper","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/35014014","article-title":"Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response","volume":"2","author":"Bertolotti","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1093\/infdis\/jiu620","article-title":"Acute phase protein \u03b11-antitrypsin reduces the bacterial burden in mice by selective modulation of innate cell responses","volume":"211","author":"Kaner","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113002","DOI":"10.18632\/oncotarget.22949","article-title":"Alpha-1-antitrypsin functions as a protective factor in preeclampsia through activating Smad2 and inhibitor of DNA binding 4","volume":"8","author":"Feng","year":"2017","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"176","DOI":"10.3389\/fphys.2016.00176","article-title":"Alpha-1 Antitrypsin Prevents the Development of Preeclampsia Through Suppression of Oxidative Stress","volume":"7","author":"Feng","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Feng, Y.L., Yin, Y.X., Ding, J., Yuan, H., Yang, L., Xu, J.J., and Hu, L.Q. (2017). Alpha-1-antitrypsin suppresses oxidative stress in preeclampsia by inhibiting the p38MAPK signaling pathway: An in vivo and in vitro study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173711"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1159\/000334820","article-title":"Alpha-1-antitrypsin acts as a preeclampsia-related protein: A proteomic study","volume":"73","author":"Feng","year":"2012","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.3109\/14767058.2012.705397","article-title":"Lower circulation levels and activity of \u03b1-1 antitrypsin in pregnant women with severe preeclampsia","volume":"25","author":"Twina","year":"2012","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"551.e1","DOI":"10.1016\/j.ajog.2008.07.006","article-title":"Proteomic profiling of urine identifies specific fragments of SERPINA1 and albumin as biomarkers of preeclampsia","volume":"199","author":"Buhimschi","year":"2008","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"245ra292","DOI":"10.1126\/scitranslmed.3008808","article-title":"Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia","volume":"6","author":"Buhimschi","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gerasimova, E.M., Fedotov, S.A., Kachkin, D.V., Vashukova, E.S., Glotov, A.S., Chernoff, Y.O., and Rubel, A.A. (2019). Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246183"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lechowicz, U., Rudzinski, S., Jezela-Stanek, A., Janciauskiene, S., and Chorostowska-Wynimko, J. (2020). Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239187"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.placenta.2016.09.005","article-title":"Endometrial androgen signaling and decidualization regulate trophoblast expansion and invasion in co-culture: A time-lapse study","volume":"47","author":"Wongwananuruk","year":"2016","journal-title":"Placenta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1071\/RD17483","article-title":"Exchange protein directly activated by cAMP (EPAC) promotes transcriptional activation of the decidual prolactin gene via CCAAT\/enhancer-binding protein in human endometrial stromal cells","volume":"30","author":"Kusama","year":"2018","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kusama, K., Miyagawa, M., Ota, K., Kuwabara, N., Saeki, K., Ohnishi, Y., Kumaki, Y., Aizawa, T., Nakasone, T., and Okamatsu, S. (2020). Cordyceps militaris Fruit Body Extract Decreases Testosterone Catabolism and Testosterone-Stimulated Prostate Hypertrophy. Nutrients, 13.","DOI":"10.3390\/nu13010050"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4918","DOI":"10.1002\/jcb.26721","article-title":"Regulation of human trophoblast cell syncytialization by transcription factors STAT5B and NR4A3","volume":"119","author":"Kusama","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1093\/humrep\/den317","article-title":"Expression of stathmin, a microtubule regulatory protein, is associated with the migration and differentiation of cultured early trophoblasts","volume":"23","author":"Yoshie","year":"2008","journal-title":"Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1530\/REP-13-0654","article-title":"Possible roles of the cAMP-mediators EPAC and RAP1 in decidualization of rat uterus","volume":"147","author":"Kusama","year":"2014","journal-title":"Reproduction"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3683\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:25:51Z","timestamp":1760361951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,1]]},"references-count":33,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22073683"],"URL":"https:\/\/doi.org\/10.3390\/ijms22073683","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,1]]}}}