Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression
The serine protease inhibitor alpha1-antitrypsin (A1AT) may possess protective functions of impaired organs in a manner independent of its protease inhibitor activity. A1AT expression has been shown to fluctuate in patients with pregnancy-induced hypertension, which suggests that A1AT may play a rol...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/4/1955 |
| _version_ | 1797479447547346944 |
|---|---|
| author | Kanoko Yoshida Aruto Yano Kazuya Kusama Gen Ishikawa Kazuhiro Tamura |
| author_facet | Kanoko Yoshida Aruto Yano Kazuya Kusama Gen Ishikawa Kazuhiro Tamura |
| author_sort | Kanoko Yoshida |
| collection | DOAJ |
| description | The serine protease inhibitor alpha1-antitrypsin (A1AT) may possess protective functions of impaired organs in a manner independent of its protease inhibitor activity. A1AT expression has been shown to fluctuate in patients with pregnancy-induced hypertension, which suggests that A1AT may play a role in the syncytialization of villous trophoblasts. A1AT expression was knocked down in primary trophoblasts. RNA was extracted from these cells and subjected to RNA-sequencing analysis to determine the levels of expression of markers of syncytialization and inflammation. In addition, A1AT protein was localized in trophoblastic cells in placental tissues. Knockdown of A1AT upregulated the expression of FOSL1 and markers of syncytialization, as well as cell fusion, whereas overexpression of A1AT had the opposite effects. FOSL1 overexpression stimulated syncytialization, similar to the effects of A1AT knock down. Inhibitors of p38MAPK and JNK reduce the expression of inflammatory factors, whereas a p38MAPK inhibitor suppressed FOSL1 expression. Collectively, these findings indicated A1AT may negatively regulate inflammatory responses by controlling the activation of p38MAPK and JNK, and that p38MAPK mediates trophoblast syncytialization by altering FOSL1 expression. Therefore, a dysfunction in A1AT could be responsible for abnormal placental formation and pregnancy-associated disorders. |
| first_indexed | 2024-03-09T21:46:00Z |
| format | Article |
| id | doaj.art-6f6e28b9dcc040c7a38e5fc4484524ac |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:46:00Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6f6e28b9dcc040c7a38e5fc4484524ac2023-11-23T20:17:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234195510.3390/ijms23041955Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor ExpressionKanoko Yoshida0Aruto Yano1Kazuya Kusama2Gen Ishikawa3Kazuhiro Tamura4Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanDepartment of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanDepartment of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanDepartment of Obstetrics, Miyagi Children’s Hospital, Sendai 989-3126, JapanDepartment of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanThe serine protease inhibitor alpha1-antitrypsin (A1AT) may possess protective functions of impaired organs in a manner independent of its protease inhibitor activity. A1AT expression has been shown to fluctuate in patients with pregnancy-induced hypertension, which suggests that A1AT may play a role in the syncytialization of villous trophoblasts. A1AT expression was knocked down in primary trophoblasts. RNA was extracted from these cells and subjected to RNA-sequencing analysis to determine the levels of expression of markers of syncytialization and inflammation. In addition, A1AT protein was localized in trophoblastic cells in placental tissues. Knockdown of A1AT upregulated the expression of FOSL1 and markers of syncytialization, as well as cell fusion, whereas overexpression of A1AT had the opposite effects. FOSL1 overexpression stimulated syncytialization, similar to the effects of A1AT knock down. Inhibitors of p38MAPK and JNK reduce the expression of inflammatory factors, whereas a p38MAPK inhibitor suppressed FOSL1 expression. Collectively, these findings indicated A1AT may negatively regulate inflammatory responses by controlling the activation of p38MAPK and JNK, and that p38MAPK mediates trophoblast syncytialization by altering FOSL1 expression. Therefore, a dysfunction in A1AT could be responsible for abnormal placental formation and pregnancy-associated disorders.https://www.mdpi.com/1422-0067/23/4/1955trophoblastssyncytializationalpha-1-antitrypsin (A1AT)FOS like 1AP-1 transcription factor subunit (FOSL1)inflammatory factor |
| spellingShingle | Kanoko Yoshida Aruto Yano Kazuya Kusama Gen Ishikawa Kazuhiro Tamura Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression International Journal of Molecular Sciences trophoblasts syncytialization alpha-1-antitrypsin (A1AT) FOS like 1 AP-1 transcription factor subunit (FOSL1) inflammatory factor |
| title | Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression |
| title_full | Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression |
| title_fullStr | Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression |
| title_full_unstemmed | Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression |
| title_short | Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression |
| title_sort | alpha 1 antitrypsin regulates trophoblast syncytialization and inflammatory factor expression |
| topic | trophoblasts syncytialization alpha-1-antitrypsin (A1AT) FOS like 1 AP-1 transcription factor subunit (FOSL1) inflammatory factor |
| url | https://www.mdpi.com/1422-0067/23/4/1955 |
| work_keys_str_mv | AT kanokoyoshida alpha1antitrypsinregulatestrophoblastsyncytializationandinflammatoryfactorexpression AT arutoyano alpha1antitrypsinregulatestrophoblastsyncytializationandinflammatoryfactorexpression AT kazuyakusama alpha1antitrypsinregulatestrophoblastsyncytializationandinflammatoryfactorexpression AT genishikawa alpha1antitrypsinregulatestrophoblastsyncytializationandinflammatoryfactorexpression AT kazuhirotamura alpha1antitrypsinregulatestrophoblastsyncytializationandinflammatoryfactorexpression |