GSK3beta Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock.
- Author:
Ryeojin KO
1
;
Hyun Duk JANG
;
Soo Young LEE
Author Information
- Publication Type:Original Article
- Keywords: GSK3beta; Peptide inhibitor; LPS; Cytokines
- MeSH: Animals; Cytokines; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Interleukin-12 Subunit p40; Interleukin-6; Interleukins; Macrophages; Mice; Peptides; Phosphorylation; Phosphotransferases; Protein Kinases; Rodentia; Serine; Shock; Shock, Septic
- From:Immune Network 2010;10(3):99-103
- CountryRepublic of Korea
- Language:English
- Abstract: BACKGROUND: Glycogen synthase kinase 3beta (GSK3beta) 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 GSK3beta inhibitors in rodent models of septic shock. Since most of the GSK3beta inhibitors are targeted at the ATP-binding site, which is highly conserved among diverse protein kinases, the development of novel non-ATP competitive GSK3beta inhibitors is needed. METHODS: Based on the unique phosphorylation motif of GSK3beta, we designed and generated a novel class of GSK3beta 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.
