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...
Published in: | PLoS Neglected Tropical Diseases |
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ftdoajarticles:oai:doaj.org/article:ccd2ff949089414687389e85f722980d 2023-05-15T15:15:05+02:00 PARK2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages. Louis de Léséleuc Marianna Orlova Aurelie Cobat Manon Girard Nguyen Thu Huong Nguyen Ngoc Ba Nguyen Van Thuc Richard Truman John S Spencer Linda Adams Vu Hong Thai Alexandre Alcais Erwin Schurr 2013-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0002015 https://doaj.org/article/ccd2ff949089414687389e85f722980d EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3547867?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002015 https://doaj.org/article/ccd2ff949089414687389e85f722980d PLoS Neglected Tropical Diseases, Vol 7, Iss 1, p e2015 (2013) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2013 ftdoajarticles https://doi.org/10.1371/journal.pntd.0002015 2022-12-31T03:38:12Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 7 1 e2015 |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Louis de Léséleuc Marianna Orlova Aurelie Cobat Manon Girard Nguyen Thu Huong Nguyen Ngoc Ba Nguyen Van Thuc Richard Truman John S Spencer Linda Adams Vu Hong Thai Alexandre Alcais Erwin Schurr PARK2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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. |
format |
Article in Journal/Newspaper |
author |
Louis de Léséleuc Marianna Orlova Aurelie Cobat Manon Girard Nguyen Thu Huong Nguyen Ngoc Ba Nguyen Van Thuc Richard Truman John S Spencer Linda Adams Vu Hong Thai Alexandre Alcais Erwin Schurr |
author_facet |
Louis de Léséleuc Marianna Orlova Aurelie Cobat Manon Girard Nguyen Thu Huong Nguyen Ngoc Ba Nguyen Van Thuc Richard Truman John S Spencer Linda Adams Vu Hong Thai Alexandre Alcais Erwin Schurr |
author_sort |
Louis de Léséleuc |
title |
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_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_sort |
park2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2013 |
url |
https://doi.org/10.1371/journal.pntd.0002015 https://doaj.org/article/ccd2ff949089414687389e85f722980d |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 7, Iss 1, p e2015 (2013) |
op_relation |
http://europepmc.org/articles/PMC3547867?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002015 https://doaj.org/article/ccd2ff949089414687389e85f722980d |
op_doi |
https://doi.org/10.1371/journal.pntd.0002015 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
7 |
container_issue |
1 |
container_start_page |
e2015 |
_version_ |
1766345459870203904 |