IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages

BACKGROUND: The cytokine environment at the site of infection is important to the control of mycobacteria by host macrophages. During chronic infection immunosuppressive cytokines are likely to favor mycobacterial growth, persistence, and an avoidance of proper antigen processing and presentation. T...

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Autores principales: Jung, Joo-Yong, Robinson, Cory M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007735/
https://www.ncbi.nlm.nih.gov/pubmed/24618498
http://dx.doi.org/10.1186/1478-811X-12-16
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author Jung, Joo-Yong
Robinson, Cory M
author_facet Jung, Joo-Yong
Robinson, Cory M
author_sort Jung, Joo-Yong
collection PubMed
description BACKGROUND: The cytokine environment at the site of infection is important to the control of mycobacteria by host macrophages. During chronic infection immunosuppressive cytokines are likely to favor mycobacterial growth, persistence, and an avoidance of proper antigen processing and presentation. The activity of interleukin (IL)-27 toward macrophages is anti-inflammatory and this compromises control of mycobacteria. Modulation of the cytokine environment may enhance both protective and vaccine-induced responses. RESULTS: In this study we showed that supplying IL-12 and neutralizing IL-27 enhanced acidification and fusion of mycobacterial-containing phagosomes with lysosomes. This was achieved by phagosomal acquisition of vacuolar ATPase (V-ATPase) and CD63. Both V-ATPase and CD63 protein levels were increased by the addition of IL-12 and neutralization of IL-27. In addition, cathepsin D associated with the bacteria and matured to the active form when IL-12 was supplied and IL-27 was neutralized. Lysosomal acidification and cathepsin D activity were associated with control of mycobacteria. The acidification of lysosomes, association with mycobacteria, and maturation of cathepsin D required macrophage production of IFN-γ and signaling through signal transducer and activator of transcription (STAT)-1. In contrast, STAT-3 signaling opposed these events. CONCLUSIONS: Our results have identified novel influences of IL-12, IL-27, and STAT-3 on lysosomal activity and further demonstrate that modulating the cytokine environment promotes enhanced trafficking of mycobacteria to lysosomes in human macrophages. This has important implications in approaches to control infection and improve vaccination. Overcoming bacterial resistance to lysosomal fusion may expand the repertoire of antigens presented to the adaptive arm of the immune response.
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spelling pubmed-40077352014-05-03 IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages Jung, Joo-Yong Robinson, Cory M Cell Commun Signal Research BACKGROUND: The cytokine environment at the site of infection is important to the control of mycobacteria by host macrophages. During chronic infection immunosuppressive cytokines are likely to favor mycobacterial growth, persistence, and an avoidance of proper antigen processing and presentation. The activity of interleukin (IL)-27 toward macrophages is anti-inflammatory and this compromises control of mycobacteria. Modulation of the cytokine environment may enhance both protective and vaccine-induced responses. RESULTS: In this study we showed that supplying IL-12 and neutralizing IL-27 enhanced acidification and fusion of mycobacterial-containing phagosomes with lysosomes. This was achieved by phagosomal acquisition of vacuolar ATPase (V-ATPase) and CD63. Both V-ATPase and CD63 protein levels were increased by the addition of IL-12 and neutralization of IL-27. In addition, cathepsin D associated with the bacteria and matured to the active form when IL-12 was supplied and IL-27 was neutralized. Lysosomal acidification and cathepsin D activity were associated with control of mycobacteria. The acidification of lysosomes, association with mycobacteria, and maturation of cathepsin D required macrophage production of IFN-γ and signaling through signal transducer and activator of transcription (STAT)-1. In contrast, STAT-3 signaling opposed these events. CONCLUSIONS: Our results have identified novel influences of IL-12, IL-27, and STAT-3 on lysosomal activity and further demonstrate that modulating the cytokine environment promotes enhanced trafficking of mycobacteria to lysosomes in human macrophages. This has important implications in approaches to control infection and improve vaccination. Overcoming bacterial resistance to lysosomal fusion may expand the repertoire of antigens presented to the adaptive arm of the immune response. BioMed Central 2014-03-11 /pmc/articles/PMC4007735/ /pubmed/24618498 http://dx.doi.org/10.1186/1478-811X-12-16 Text en Copyright © 2014 Jung and Robinson; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Jung, Joo-Yong
Robinson, Cory M
IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages
title IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages
title_full IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages
title_fullStr IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages
title_full_unstemmed IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages
title_short IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages
title_sort il-12 and il-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007735/
https://www.ncbi.nlm.nih.gov/pubmed/24618498
http://dx.doi.org/10.1186/1478-811X-12-16
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