Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Ko, Ryeojin, Jang, Hyun Duk, Lee, Soo Young
Formato: Texto
Lenguaje:English
Publicado: The Korean Association of Immunologists 2010
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
_version_ 1782183782687703040
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
work_keys_str_mv AT koryeojin gsk3binhibitorpeptideprotectsmicefromlpsinducedendotoxinshock
AT janghyunduk gsk3binhibitorpeptideprotectsmicefromlpsinducedendotoxinshock
AT leesooyoung gsk3binhibitorpeptideprotectsmicefromlpsinducedendotoxinshock