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The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages
Toll-like receptors (TLR) 7 and 9 transduce a cellular signal through the MyD88-dependent pathway and induce the production of inflammatory mediators against microbial nucleotide components. The repeated stimulation of TLR4 leads to endotoxin tolerance, but the molecular mechanisms of tolerance indu...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Korean Society for Molecular and Cellular Biology
2015
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314129/ https://www.ncbi.nlm.nih.gov/pubmed/25518931 http://dx.doi.org/10.14348/molcells.2015.2136 |
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author | Lee, Hyo-Ji Kim, Keun-Cheol Han, Jeong A Choi, Sun Shim Jung, Yu-Jin |
author_facet | Lee, Hyo-Ji Kim, Keun-Cheol Han, Jeong A Choi, Sun Shim Jung, Yu-Jin |
author_sort | Lee, Hyo-Ji |
collection | PubMed |
description | Toll-like receptors (TLR) 7 and 9 transduce a cellular signal through the MyD88-dependent pathway and induce the production of inflammatory mediators against microbial nucleotide components. The repeated stimulation of TLR4 leads to endotoxin tolerance, but the molecular mechanisms of tolerance induced through the costimulation of individual TLR has not yet been established, although endosomal TLRs share signaling pathways with TLR4. In the present study, mouse macrophages were simultaneously stimulated with the TLR7 agonist, gardiquimod (GDQ), and the TLR9 agonist, CpG ODN 1826, to examine the mechanism and effector functions of macrophage tolerance. Compared with individual stimulation, the costimulation of both TLRs reduced the secretion of TNF-α and IL-6 through the delayed activation of the NF-κB pathway; notably, IL-10 remained unchanged in costimulated macrophages. This tolerance reflected the early induction of suppressor of cytokine signaling-1 (SOCS-1), according to the detection of elevated TNF-α secretion and restored NF-κB signaling in response to the siRNA-mediated abrogation of SOCS-1 signaling. In addition, the restimulation of each TLRs using the same ligand significantly reduced the expression of both TLRs in endosomes. These findings revealed that the costimulation of TLR7 and TLR9 induced macrophage tolerance via SOCS-1, and the restimulation of each receptor or both TLR7 and TLR9 downregulated TLR expression through a negative feedback mechanisms that protects the host from excessive inflammatory responses. Moreover, the insufficient and impaired immune response in chronic viral infection might also reflect the repeated and simultaneous stimulation of those endosomal TLRs. |
format | Online Article Text |
id | pubmed-4314129 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Korean Society for Molecular and Cellular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-43141292015-02-10 The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages Lee, Hyo-Ji Kim, Keun-Cheol Han, Jeong A Choi, Sun Shim Jung, Yu-Jin Mol Cells Article Toll-like receptors (TLR) 7 and 9 transduce a cellular signal through the MyD88-dependent pathway and induce the production of inflammatory mediators against microbial nucleotide components. The repeated stimulation of TLR4 leads to endotoxin tolerance, but the molecular mechanisms of tolerance induced through the costimulation of individual TLR has not yet been established, although endosomal TLRs share signaling pathways with TLR4. In the present study, mouse macrophages were simultaneously stimulated with the TLR7 agonist, gardiquimod (GDQ), and the TLR9 agonist, CpG ODN 1826, to examine the mechanism and effector functions of macrophage tolerance. Compared with individual stimulation, the costimulation of both TLRs reduced the secretion of TNF-α and IL-6 through the delayed activation of the NF-κB pathway; notably, IL-10 remained unchanged in costimulated macrophages. This tolerance reflected the early induction of suppressor of cytokine signaling-1 (SOCS-1), according to the detection of elevated TNF-α secretion and restored NF-κB signaling in response to the siRNA-mediated abrogation of SOCS-1 signaling. In addition, the restimulation of each TLRs using the same ligand significantly reduced the expression of both TLRs in endosomes. These findings revealed that the costimulation of TLR7 and TLR9 induced macrophage tolerance via SOCS-1, and the restimulation of each receptor or both TLR7 and TLR9 downregulated TLR expression through a negative feedback mechanisms that protects the host from excessive inflammatory responses. Moreover, the insufficient and impaired immune response in chronic viral infection might also reflect the repeated and simultaneous stimulation of those endosomal TLRs. Korean Society for Molecular and Cellular Biology 2015-01-31 2014-12-15 /pmc/articles/PMC4314129/ /pubmed/25518931 http://dx.doi.org/10.14348/molcells.2015.2136 Text en © The Korean Society for Molecular and Cellular Biology. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/. |
spellingShingle | Article Lee, Hyo-Ji Kim, Keun-Cheol Han, Jeong A Choi, Sun Shim Jung, Yu-Jin The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages |
title | The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages |
title_full | The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages |
title_fullStr | The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages |
title_full_unstemmed | The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages |
title_short | The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages |
title_sort | early induction of suppressor of cytokine signaling 1 and the downregulation of toll-like receptors 7 and 9 induce tolerance in costimulated macrophages |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314129/ https://www.ncbi.nlm.nih.gov/pubmed/25518931 http://dx.doi.org/10.14348/molcells.2015.2136 |
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