Cargando…

Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice

Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine meta...

Descripción completa

Detalles Bibliográficos
Autores principales: Ueda, Yo, Saegusa, Jun, Okano, Takaichi, Sendo, Sho, Yamada, Hirotaka, Nishimura, Keisuke, Morinobu, Akio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476881/
https://www.ncbi.nlm.nih.gov/pubmed/31011190
http://dx.doi.org/10.1038/s41598-019-42932-1
_version_ 1783412951844126720
author Ueda, Yo
Saegusa, Jun
Okano, Takaichi
Sendo, Sho
Yamada, Hirotaka
Nishimura, Keisuke
Morinobu, Akio
author_facet Ueda, Yo
Saegusa, Jun
Okano, Takaichi
Sendo, Sho
Yamada, Hirotaka
Nishimura, Keisuke
Morinobu, Akio
author_sort Ueda, Yo
collection PubMed
description Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4(+) T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G(+) granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4(+) T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4(+) T and Th17 cells in the spleen were lowest in mice treated with the combination therapy. Thus, combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4(+) T cell proliferation and Th17 differentiation. These results suggest the combination of rapamycin and DON may be a potential novel therapy for arthritis.
format Online
Article
Text
id pubmed-6476881
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-64768812019-05-02 Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice Ueda, Yo Saegusa, Jun Okano, Takaichi Sendo, Sho Yamada, Hirotaka Nishimura, Keisuke Morinobu, Akio Sci Rep Article Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4(+) T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G(+) granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4(+) T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4(+) T and Th17 cells in the spleen were lowest in mice treated with the combination therapy. Thus, combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4(+) T cell proliferation and Th17 differentiation. These results suggest the combination of rapamycin and DON may be a potential novel therapy for arthritis. Nature Publishing Group UK 2019-04-23 /pmc/articles/PMC6476881/ /pubmed/31011190 http://dx.doi.org/10.1038/s41598-019-42932-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ueda, Yo
Saegusa, Jun
Okano, Takaichi
Sendo, Sho
Yamada, Hirotaka
Nishimura, Keisuke
Morinobu, Akio
Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice
title Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice
title_full Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice
title_fullStr Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice
title_full_unstemmed Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice
title_short Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice
title_sort additive effects of inhibiting both mtor and glutamine metabolism on the arthritis in skg mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476881/
https://www.ncbi.nlm.nih.gov/pubmed/31011190
http://dx.doi.org/10.1038/s41598-019-42932-1
work_keys_str_mv AT uedayo additiveeffectsofinhibitingbothmtorandglutaminemetabolismonthearthritisinskgmice
AT saegusajun additiveeffectsofinhibitingbothmtorandglutaminemetabolismonthearthritisinskgmice
AT okanotakaichi additiveeffectsofinhibitingbothmtorandglutaminemetabolismonthearthritisinskgmice
AT sendosho additiveeffectsofinhibitingbothmtorandglutaminemetabolismonthearthritisinskgmice
AT yamadahirotaka additiveeffectsofinhibitingbothmtorandglutaminemetabolismonthearthritisinskgmice
AT nishimurakeisuke additiveeffectsofinhibitingbothmtorandglutaminemetabolismonthearthritisinskgmice
AT morinobuakio additiveeffectsofinhibitingbothmtorandglutaminemetabolismonthearthritisinskgmice