Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase
In organ transplantation, donor‐specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor‐specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvagi...
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doaj-c90ab764cb124b8291a80381c0642fd12020-11-25T03:44:57ZengWileyFEBS Open Bio2211-54632020-05-0110592793610.1002/2211-5463.12854Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductaseAkihiro Maenaka0Iwasaki Kenta1Akinobu Ota2Yuko Miwa3Wataru Ohashi4Kosei Horimi5Yutaka Matsuoka6Masafumi Ohnishi7Kazuharu Uchida8Takaaki Kobayashi9Department of Pharmacy Aichi Medical University School of Medicine Nagakute JapanDepartment of Kidney Disease and Transplant Immunology Aichi Medical University School of Medicine Nagakute JapanDepartment of Biochemistry Aichi Medical University School of Medicine Nagakute JapanDepartment of Kidney Disease and Transplant Immunology Aichi Medical University School of Medicine Nagakute JapanDivision of Biostatistics Clinical Research Center Aichi Medical University School of Medicine Nagakute JapanDepartment of Renal Transplant Surgery Aichi Medical University School of Medicine Nagakute JapanDepartment of Renal Transplant Surgery Aichi Medical University School of Medicine Nagakute JapanDepartment of Pharmacy Aichi Medical University School of Medicine Nagakute JapanDepartment of Kidney Disease and Transplant Immunology Aichi Medical University School of Medicine Nagakute JapanDepartment of Renal Transplant Surgery Aichi Medical University School of Medicine Nagakute JapanIn organ transplantation, donor‐specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor‐specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvaging DSA‐mediated graft rejection. We examined the effect of various clinically used drugs on HLA class II expression on endothelial cells. Interferon‐γ (IFN‐γ)‐induced HLA class II DR (HLA‐DR) was downregulated by everolimus (EVR, 49.1% ± 0.8%; P < 0.01) and fluvastatin (FLU, 33.8% ± 0.6%; P < 0.01). Moreover, the combination of EVR and FLU showed a greater suppressive effect on HLA‐DR expression. In contrast, cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA‐DR. Imaging analysis revealed that HLA‐DR expressed in cytosol or on the cell surface was repressed by EVR (cytosol: 58.6% ± 4.9%, P < 0.01; cell surface: 80.9% ± 4.0%, P < 0.01) and FLU (cytosol: 19.0% ± 3.4%, P < 0.01; cell surface: 48.3% ± 4.8%, P < 0.01). These data indicated that FLU and EVR suppressed IFN‐γ‐induced HLA‐DR expression at the transcriptional and post‐translational level, respectively, suggesting a potential approach for alleviating DSA‐related issues in organ transplantation.https://doi.org/10.1002/2211-5463.12854CIITAendothelial celleverolimusfluvastatinHLA class II |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Akihiro Maenaka Iwasaki Kenta Akinobu Ota Yuko Miwa Wataru Ohashi Kosei Horimi Yutaka Matsuoka Masafumi Ohnishi Kazuharu Uchida Takaaki Kobayashi |
spellingShingle |
Akihiro Maenaka Iwasaki Kenta Akinobu Ota Yuko Miwa Wataru Ohashi Kosei Horimi Yutaka Matsuoka Masafumi Ohnishi Kazuharu Uchida Takaaki Kobayashi Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase FEBS Open Bio CIITA endothelial cell everolimus fluvastatin HLA class II |
author_facet |
Akihiro Maenaka Iwasaki Kenta Akinobu Ota Yuko Miwa Wataru Ohashi Kosei Horimi Yutaka Matsuoka Masafumi Ohnishi Kazuharu Uchida Takaaki Kobayashi |
author_sort |
Akihiro Maenaka |
title |
Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase |
title_short |
Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase |
title_full |
Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase |
title_fullStr |
Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase |
title_full_unstemmed |
Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase |
title_sort |
interferon‐γ‐induced hla class ii expression on endothelial cells is decreased by inhibition of mtor and hmg‐coa reductase |
publisher |
Wiley |
series |
FEBS Open Bio |
issn |
2211-5463 |
publishDate |
2020-05-01 |
description |
In organ transplantation, donor‐specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor‐specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvaging DSA‐mediated graft rejection. We examined the effect of various clinically used drugs on HLA class II expression on endothelial cells. Interferon‐γ (IFN‐γ)‐induced HLA class II DR (HLA‐DR) was downregulated by everolimus (EVR, 49.1% ± 0.8%; P < 0.01) and fluvastatin (FLU, 33.8% ± 0.6%; P < 0.01). Moreover, the combination of EVR and FLU showed a greater suppressive effect on HLA‐DR expression. In contrast, cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA‐DR. Imaging analysis revealed that HLA‐DR expressed in cytosol or on the cell surface was repressed by EVR (cytosol: 58.6% ± 4.9%, P < 0.01; cell surface: 80.9% ± 4.0%, P < 0.01) and FLU (cytosol: 19.0% ± 3.4%, P < 0.01; cell surface: 48.3% ± 4.8%, P < 0.01). These data indicated that FLU and EVR suppressed IFN‐γ‐induced HLA‐DR expression at the transcriptional and post‐translational level, respectively, suggesting a potential approach for alleviating DSA‐related issues in organ transplantation. |
topic |
CIITA endothelial cell everolimus fluvastatin HLA class II |
url |
https://doi.org/10.1002/2211-5463.12854 |
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