title: Endoplasmic reticulum aminopeptidase-1 mediates leukemia inhibitory factor-induced cell surface human leukocyte antigen-G expression in JEG-3 choriocarcinoma cells.
abstract: Maternal immune tolerance is required for extravillous trophoblasts (EVTs) to invade the decidua without rejection. Endoplasmic reticulum aminopeptidase-1 (ERAP1) generates human leukocyte antigen (HLA) class I-adapted antigenic peptides, but its function in trophoblasts lacking classical HLA class I molecules remains undetermined. Leukemia inhibitory factor (LIF) is produced from decidua during the implantation period and plays a necessary role in establishing pregnancy. This study is intended to investigate the location and the function of ERAP1 in trophoblastic cells, focusing on LIF. Immunohistochemistry showed strong ERAP1 expression in cultured EVTs. In choriocarcinoma cell lines used as a model for trophoblasts, ERAP1 was expressed more intensively in JEG-3 than BeWo cells. Immunoblot analysis and immunocytochemistry localized ERAP1 to the endoplasmic reticulum (ER) in JEG-3 cells. Flow cytometry with HLA-G antibody to monitor the supply of antigenic peptides presenting to HLA-G in the ER showed that reducing ERAP1 transcripts by RNA interference did not affect cell surface expression of membrane HLA-G1 (mHLA-G1) in JEG-3 cells under basal conditions. In LIF-treated JEG-3 cells, cell surface mHLA-G1 expression was increased along with ERAP1 protein and promoter activities. In contrast to nonstimulated cells, eliminating ERAP1 from LIF-treated JEG-3 cells reduced the cell surface mHLA-G1 expression and soluble HLA-G1 secretion. This study provides the first evidence showing that ERAP1 is localized in the ER of trophoblasts and is involved in regulating cell surface HLA-G expression in the presence of LIF. Consequently, ERAP1 would function to present antigenic peptides to HLA-G in trophoblasts.
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Shido
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ito
authors.forename: Seiji
authors.initials: S
authors.lastname: Nomura
authors.forename: Eiko
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Sumigama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ino
authors.forename: Atsuo
authors.initials: A
authors.lastname: Itakura
authors.forename: Akira
authors.initials: A
authors.lastname: Hattori
authors.forename: Masafumi
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Mizutani
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
mesh_terms: D000626:Aminopeptidases / Q000032:analysis / Q000502:physiology*; D017951:Antigen Presentation; D002462:Cell Membrane / Q000276:immunology; D002822:Choriocarcinoma / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D005260:Female; D006680:HLA Antigens / Q000032:analysis*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering / Q000494:pharmacology; D014327:Trophoblasts / Q000201:enzymology / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; D000626:Aminopeptidases; C464841:ERAP1 protein, human