PMID- 16601113
OWN - NLM
STAT- MEDLINE
DCOM- 20060811
LR  - 20210314
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 281
IP  - 25
DP  - 2006 Jun 23
TI  - Novel anti-inflammatory role for glycogen synthase kinase-3beta in the inhibition 
      of tumor necrosis factor-alpha- and interleukin-1beta-induced inflammatory gene 
      expression.
PG  - 16985-16990
LID - S0021-9258(20)55723-2 [pii]
LID - 10.1074/jbc.M602446200 [doi]
AB  - Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine kinase with a 
      broad array of cellular targets, such as cytoskeletal proteins and transcription 
      factors. Recent studies with GSK-3beta-null mice showed impaired 
      NFkappaB-mediated survival responses. Because NFkappaB serves a dual role as a 
      key regulator of cytokine-induced inflammatory gene expression and apoptosis, we 
      investigated whether modulation of GSK-3beta expression affects cytokine-induced 
      and NFkappaB-mediated inflammatory gene expression. We observed that tumor 
      necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) treatment of 
      primary cultures of human microvascular cells reduced net endogenous active 
      GSK-3beta protein levels while inducing inflammatory cytokine (IL-6 and monocyte 
      chemoattractant protein-1 (MCP-1)) expression. Interestingly, inhibition of 
      GSK-3beta by antisense oligonucleotides or pharmacological agent (10 mm lithium) 
      potentiated TNF-induced expression of IL-6 and MCP-1 by 2-6-fold suggesting that 
      inhibition of GSK-3beta under inflammatory conditions (exposure to TNF-alpha and 
      IL-1beta) may contribute to enhanced cytokine expression. Overexpression of 
      GSK-3beta in endothelial cells, in contrast, significantly inhibited (by 70%, p < 
      0.01) both TNF-alpha and IL-1beta-induced expression of IL-6, MCP-1, and vascular 
      cell adhesion molecule-1. Using adenoviruses in lipopolysaccharide-stimulated 
      mice, overexpression of GSK-3beta significantly decreased TNF-alpha expression in 
      lung and heart tissues (38 and 15%, respectively), further confirming the 
      anti-inflammatory role of GSK-3beta. Overexpression of GSK-3beta did not affect 
      the TNF-alpha-induced nuclear translocation of NFkappaB but reduced the nuclear 
      half-life of TNF-alpha-induced NFkappaB considerably (by as much as 9 h) and 
      enhanced phosphorylation (by as much as 33%). Interestingly, neither endothelial 
      cell survival nor NFkappaB-mediated expression of anti-apoptotic genes was 
      affected by GSK-3beta overexpression. We conclude that GSK-3beta selectively 
      regulates NFkappaB-mediated inflammatory gene expression by controlling the flow 
      of NFkappaB activity between transcription of inflammatory and survival genes.
FAU - Vines, Angela
AU  - Vines A
AD  - Reddy US Therapeutics, Dr. Reddy's Laboratories, Norcross, Georgia 30071. 
      Electronic address: avines@reddyus.com.
FAU - Cahoon, Sientay
AU  - Cahoon S
AD  - Reddy US Therapeutics, Dr. Reddy's Laboratories, Norcross, Georgia 30071.
FAU - Goldberg, Ira
AU  - Goldberg I
AD  - Department of Medicine, Columbia University, New York, New York 10032.
FAU - Saxena, Uday
AU  - Saxena U
AD  - Reddy US Therapeutics, Dr. Reddy's Laboratories, Norcross, Georgia 30071.
FAU - Pillarisetti, Sivaram
AU  - Pillarisetti S
AD  - Reddy US Therapeutics, Dr. Reddy's Laboratories, Norcross, Georgia 30071.
LA  - eng
PT  - Journal Article
DEP - 20060406
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-1)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Active Transport, Cell Nucleus
MH  - Animals
MH  - Anti-Inflammatory Agents/*metabolism
MH  - Apoptosis
MH  - Cell Line
MH  - Chemokine CCL2/metabolism
MH  - Endothelium, Vascular/metabolism
MH  - Glycogen Synthase Kinase 3/metabolism/*physiology
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Interleukin-1/*metabolism
MH  - Interleukin-6/metabolism
MH  - Lipopolysaccharides/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Tumor Necrosis Factor-alpha/*metabolism
EDAT- 2006/04/08 09:00
MHDA- 2006/08/12 09:00
CRDT- 2006/04/08 09:00
PHST- 2006/04/08 09:00 [pubmed]
PHST- 2006/08/12 09:00 [medline]
PHST- 2006/04/08 09:00 [entrez]
AID - S0021-9258(20)55723-2 [pii]
AID - 10.1074/jbc.M602446200 [doi]
PST - ppublish
SO  - J Biol Chem. 2006 Jun 23;281(25):16985-16990. doi: 10.1074/jbc.M602446200. Epub 
      2006 Apr 6.