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PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages

Leprosy is a persistent infectious disease caused by Mycobacterium leprae that still affects over 200,000 new patients annually. The host genetic background is an important risk factor for leprosy susceptibility and the PARK2 gene is a replicated leprosy susceptibility candidate gene. The protein pr...

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Autores principales: de Léséleuc, Louis, Orlova, Marianna, Cobat, Aurelie, Girard, Manon, Huong, Nguyen Thu, Ba, Nguyen Ngoc, Van Thuc, Nguyen, Truman, Richard, Spencer, John S., Adams, Linda, Thai, Vu Hong, Alcais, Alexandre, Schurr, Erwin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547867/
https://www.ncbi.nlm.nih.gov/pubmed/23350010
http://dx.doi.org/10.1371/journal.pntd.0002015
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author de Léséleuc, Louis
Orlova, Marianna
Cobat, Aurelie
Girard, Manon
Huong, Nguyen Thu
Ba, Nguyen Ngoc
Van Thuc, Nguyen
Truman, Richard
Spencer, John S.
Adams, Linda
Thai, Vu Hong
Alcais, Alexandre
Schurr, Erwin
author_facet de Léséleuc, Louis
Orlova, Marianna
Cobat, Aurelie
Girard, Manon
Huong, Nguyen Thu
Ba, Nguyen Ngoc
Van Thuc, Nguyen
Truman, Richard
Spencer, John S.
Adams, Linda
Thai, Vu Hong
Alcais, Alexandre
Schurr, Erwin
author_sort de Léséleuc, Louis
collection PubMed
description Leprosy is a persistent infectious disease caused by Mycobacterium leprae that still affects over 200,000 new patients annually. The host genetic background is an important risk factor for leprosy susceptibility and the PARK2 gene is a replicated leprosy susceptibility candidate gene. The protein product of PARK2, Parkin, is an E3 ubiquitin ligase that is involved in the development of various forms of Parkinsonism. The human macrophage is both a natural host cell of M. leprae as well as a primary mediator of natural immune defenses, in part by secreting important pro-inflammatory cytokines and chemokines. Here, we report that down-regulation of Parkin in THP-1 macrophages, human monocyte-derived macrophages and human Schwann cells resulted in a consistent and specific decrease in interleukin-6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1/CCL2) production in response to mycobacteria or LPS. Interestingly, production of IL-6 at 6 hours by THP-1 cells stimulated with live M. leprae and M. bovis BCG was dependent on pretreatment with 1,25-dihydroxyvitamin D(3) (VD). Parkin knockdown in VD-treated cells blocked IL-6 induction by mycobacteria. However, IκB-α phosphorylation and levels of IκB-ξ, a nuclear protein required for IL-6 expression, were not affected by Parkin silencing. Phosphorylation of MAPK ERK1/2 and p38 was unaffected by Parkin silencing while JNK activation was promoted but did not explain the altered cytokine production. In a final set of experiments we found that genetic risk factors of leprosy located in the PARK2 promoter region were significantly correlated with M. leprae sonicate triggered CCL2 and IL6 transcript levels in whole blood assays. These results associated genetically controlled changes in the production of MCP-1/CCL2 and IL-6 with known leprosy susceptibility factors.
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spelling pubmed-35478672013-01-24 PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages de Léséleuc, Louis Orlova, Marianna Cobat, Aurelie Girard, Manon Huong, Nguyen Thu Ba, Nguyen Ngoc Van Thuc, Nguyen Truman, Richard Spencer, John S. Adams, Linda Thai, Vu Hong Alcais, Alexandre Schurr, Erwin PLoS Negl Trop Dis Research Article Leprosy is a persistent infectious disease caused by Mycobacterium leprae that still affects over 200,000 new patients annually. The host genetic background is an important risk factor for leprosy susceptibility and the PARK2 gene is a replicated leprosy susceptibility candidate gene. The protein product of PARK2, Parkin, is an E3 ubiquitin ligase that is involved in the development of various forms of Parkinsonism. The human macrophage is both a natural host cell of M. leprae as well as a primary mediator of natural immune defenses, in part by secreting important pro-inflammatory cytokines and chemokines. Here, we report that down-regulation of Parkin in THP-1 macrophages, human monocyte-derived macrophages and human Schwann cells resulted in a consistent and specific decrease in interleukin-6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1/CCL2) production in response to mycobacteria or LPS. Interestingly, production of IL-6 at 6 hours by THP-1 cells stimulated with live M. leprae and M. bovis BCG was dependent on pretreatment with 1,25-dihydroxyvitamin D(3) (VD). Parkin knockdown in VD-treated cells blocked IL-6 induction by mycobacteria. However, IκB-α phosphorylation and levels of IκB-ξ, a nuclear protein required for IL-6 expression, were not affected by Parkin silencing. Phosphorylation of MAPK ERK1/2 and p38 was unaffected by Parkin silencing while JNK activation was promoted but did not explain the altered cytokine production. In a final set of experiments we found that genetic risk factors of leprosy located in the PARK2 promoter region were significantly correlated with M. leprae sonicate triggered CCL2 and IL6 transcript levels in whole blood assays. These results associated genetically controlled changes in the production of MCP-1/CCL2 and IL-6 with known leprosy susceptibility factors. Public Library of Science 2013-01-17 /pmc/articles/PMC3547867/ /pubmed/23350010 http://dx.doi.org/10.1371/journal.pntd.0002015 Text en © 2013 de Léséleuc et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
de Léséleuc, Louis
Orlova, Marianna
Cobat, Aurelie
Girard, Manon
Huong, Nguyen Thu
Ba, Nguyen Ngoc
Van Thuc, Nguyen
Truman, Richard
Spencer, John S.
Adams, Linda
Thai, Vu Hong
Alcais, Alexandre
Schurr, Erwin
PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages
title PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages
title_full PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages
title_fullStr PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages
title_full_unstemmed PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages
title_short PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages
title_sort park2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547867/
https://www.ncbi.nlm.nih.gov/pubmed/23350010
http://dx.doi.org/10.1371/journal.pntd.0002015
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