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TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant
High mobility group box protein 1 (HMGB1) acts as an endogenous danger molecule that is released from necrotic cells and activated macrophages. We have previously shown that peptide Hp91, whose sequence corresponds to an area within the B-Box domain of HMGB1, activates dendritic cells (DCs) and acts...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261565/ https://www.ncbi.nlm.nih.gov/pubmed/25123824 http://dx.doi.org/10.1186/1479-5876-12-211 |
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author | Saenz, Rebecca Futalan, Diahnn Leutenez, Lien Eekhout, Fien Fecteau, Jessie F Sundelius, Simeon Sundqvist, Stig Larsson, Marie Hayashi, Tomoko Minev, Boris Carson, Dennis Esener, Sadik Messmer, Bradley Messmer, Davorka |
author_facet | Saenz, Rebecca Futalan, Diahnn Leutenez, Lien Eekhout, Fien Fecteau, Jessie F Sundelius, Simeon Sundqvist, Stig Larsson, Marie Hayashi, Tomoko Minev, Boris Carson, Dennis Esener, Sadik Messmer, Bradley Messmer, Davorka |
author_sort | Saenz, Rebecca |
collection | PubMed |
description | High mobility group box protein 1 (HMGB1) acts as an endogenous danger molecule that is released from necrotic cells and activated macrophages. We have previously shown that peptide Hp91, whose sequence corresponds to an area within the B-Box domain of HMGB1, activates dendritic cells (DCs) and acts as an adjuvant in vivo. Here we investigated the underlying mechanisms of Hp91-mediated DC activation. Hp91-induced secretion of IL-6 was dependent on clathrin- and dynamin-driven endocytosis of Hp91 and mediated through a MyD88- and TLR4-dependent pathway involving p38 MAPK and NFκB. Endosomal TLR4 has been shown to activate the MyD88-independent interferon pathway. Hp91-induced activation of pIRF3 and IL-6 secretion was reduced in IFNαβR knockout DCs, suggesting an amplification loop via the IFNαβR. These findings elucidate the mechanisms by which Hp91 acts as immunostimulatory peptide and may serve as a guide for the future development of synthetic Th1-type peptide adjuvants for vaccines. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1479-5876-12-211) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4261565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42615652014-12-10 TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant Saenz, Rebecca Futalan, Diahnn Leutenez, Lien Eekhout, Fien Fecteau, Jessie F Sundelius, Simeon Sundqvist, Stig Larsson, Marie Hayashi, Tomoko Minev, Boris Carson, Dennis Esener, Sadik Messmer, Bradley Messmer, Davorka J Transl Med Research High mobility group box protein 1 (HMGB1) acts as an endogenous danger molecule that is released from necrotic cells and activated macrophages. We have previously shown that peptide Hp91, whose sequence corresponds to an area within the B-Box domain of HMGB1, activates dendritic cells (DCs) and acts as an adjuvant in vivo. Here we investigated the underlying mechanisms of Hp91-mediated DC activation. Hp91-induced secretion of IL-6 was dependent on clathrin- and dynamin-driven endocytosis of Hp91 and mediated through a MyD88- and TLR4-dependent pathway involving p38 MAPK and NFκB. Endosomal TLR4 has been shown to activate the MyD88-independent interferon pathway. Hp91-induced activation of pIRF3 and IL-6 secretion was reduced in IFNαβR knockout DCs, suggesting an amplification loop via the IFNαβR. These findings elucidate the mechanisms by which Hp91 acts as immunostimulatory peptide and may serve as a guide for the future development of synthetic Th1-type peptide adjuvants for vaccines. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1479-5876-12-211) contains supplementary material, which is available to authorized users. BioMed Central 2014-08-14 /pmc/articles/PMC4261565/ /pubmed/25123824 http://dx.doi.org/10.1186/1479-5876-12-211 Text en © Saenz et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), 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 Saenz, Rebecca Futalan, Diahnn Leutenez, Lien Eekhout, Fien Fecteau, Jessie F Sundelius, Simeon Sundqvist, Stig Larsson, Marie Hayashi, Tomoko Minev, Boris Carson, Dennis Esener, Sadik Messmer, Bradley Messmer, Davorka TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant |
title | TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant |
title_full | TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant |
title_fullStr | TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant |
title_full_unstemmed | TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant |
title_short | TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant |
title_sort | tlr4-dependent activation of dendritic cells by an hmgb1-derived peptide adjuvant |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261565/ https://www.ncbi.nlm.nih.gov/pubmed/25123824 http://dx.doi.org/10.1186/1479-5876-12-211 |
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