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Alpha-1 Antitrypsin-Induced Endoplasmic Reticulum Stress Promotes Invasion by Extravillous Trophoblasts

Authors :
Kiyoko Kato
Takako Ohmaru-Nakanishi
Kazuhiro Tamura
Kazuya Kusama
Kanoko Yoshida
Yuta Fukushima
Source :
International Journal of Molecular Sciences, Vol 22, Iss 3683, p 3683 (2021), International Journal of Molecular Sciences, Volume 22, Issue 7
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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–fetal interface might cause abnormal placental development.

Details

Language :
English
ISSN :
16616596 and 14220067
Volume :
22
Issue :
3683
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences
Accession number :
edsair.doi.dedup.....574461dad3253378a1bab50ff0cccf2c