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GSK3β Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock
BACKGROUND: Glycogen synthase kinase 3β (GSK3β) is a ubiquitous serine/threonine kinase that is regulated by serine phosphorylation at 9. Recent studies have reported the beneficial effects of a number of the pharmacological GSK3β inhibitors in rodent models of septic shock. Since most of the GSK3β...
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Formato: | Texto |
Lenguaje: | English |
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The Korean Association of Immunologists
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902676/ https://www.ncbi.nlm.nih.gov/pubmed/20631880 http://dx.doi.org/10.4110/in.2010.10.3.99 |
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author | Ko, Ryeojin Jang, Hyun Duk Lee, Soo Young |
author_facet | Ko, Ryeojin Jang, Hyun Duk Lee, Soo Young |
author_sort | Ko, Ryeojin |
collection | PubMed |
description | BACKGROUND: Glycogen synthase kinase 3β (GSK3β) is a ubiquitous serine/threonine kinase that is regulated by serine phosphorylation at 9. Recent studies have reported the beneficial effects of a number of the pharmacological GSK3β inhibitors in rodent models of septic shock. Since most of the GSK3β inhibitors are targeted at the ATP-binding site, which is highly conserved among diverse protein kinases, the development of novel non-ATP competitive GSK3β inhibitors is needed. METHODS: Based on the unique phosphorylation motif of GSK3β, we designed and generated a novel class of GSK3β inhibitor (GSK3i) peptides. In addition, we investigated the effects of a GSK3i peptide on lipopolysaccharide (LPS)-stimulated cytokine production and septic shock. Mice were intraperitoneally injected with GSK3i peptide and monitored over a 7-day period for survival. RESULTS: We first demonstrate its effects on LPS-stimulated pro-inflammatory cytokine production including interleukin (IL)-6 and IL-12p40. LPS-induced IL-6 and IL-12p40 production in macrophages was suppressed when macrophages were treated with the GSKi peptide. Administration of the GSK3i peptide potently suppressed LPS-mediated endotoxin shock. CONCLUSION: Collectively, we present a rational strategy for the development of a therapeutic GSK3i peptide. This peptide may serve as a novel template for the design of non-ATP competitive GSK3 inhibitors. |
format | Text |
id | pubmed-2902676 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The Korean Association of Immunologists |
record_format | MEDLINE/PubMed |
spelling | pubmed-29026762010-07-14 GSK3β Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock Ko, Ryeojin Jang, Hyun Duk Lee, Soo Young Immune Netw Original Article BACKGROUND: Glycogen synthase kinase 3β (GSK3β) is a ubiquitous serine/threonine kinase that is regulated by serine phosphorylation at 9. Recent studies have reported the beneficial effects of a number of the pharmacological GSK3β inhibitors in rodent models of septic shock. Since most of the GSK3β inhibitors are targeted at the ATP-binding site, which is highly conserved among diverse protein kinases, the development of novel non-ATP competitive GSK3β inhibitors is needed. METHODS: Based on the unique phosphorylation motif of GSK3β, we designed and generated a novel class of GSK3β inhibitor (GSK3i) peptides. In addition, we investigated the effects of a GSK3i peptide on lipopolysaccharide (LPS)-stimulated cytokine production and septic shock. Mice were intraperitoneally injected with GSK3i peptide and monitored over a 7-day period for survival. RESULTS: We first demonstrate its effects on LPS-stimulated pro-inflammatory cytokine production including interleukin (IL)-6 and IL-12p40. LPS-induced IL-6 and IL-12p40 production in macrophages was suppressed when macrophages were treated with the GSKi peptide. Administration of the GSK3i peptide potently suppressed LPS-mediated endotoxin shock. CONCLUSION: Collectively, we present a rational strategy for the development of a therapeutic GSK3i peptide. This peptide may serve as a novel template for the design of non-ATP competitive GSK3 inhibitors. The Korean Association of Immunologists 2010-06 2010-06-30 /pmc/articles/PMC2902676/ /pubmed/20631880 http://dx.doi.org/10.4110/in.2010.10.3.99 Text en Copyright © 2010 The Korean Association of Immunologists http://creativecommons.org/licenses/by-nc/3.0 This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Ko, Ryeojin Jang, Hyun Duk Lee, Soo Young GSK3β Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock |
title | GSK3β Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock |
title_full | GSK3β Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock |
title_fullStr | GSK3β Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock |
title_full_unstemmed | GSK3β Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock |
title_short | GSK3β Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock |
title_sort | gsk3β inhibitor peptide protects mice from lps-induced endotoxin shock |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902676/ https://www.ncbi.nlm.nih.gov/pubmed/20631880 http://dx.doi.org/10.4110/in.2010.10.3.99 |
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