Glycogen synthase kinase 3-β: a master regulator of toll-like receptor-mediated chronic intestinal inflammation.
BACKGROUND
A disturbed regulation of Toll-like receptor (TLR) signal transduction resulting in the exclusive activation of proinflammatory signaling pathways may be critical for the perpetuation of established chronic colitis. Glycogen synthase kinase 3-β (GSK3-β) was recently identified as an important regulator of TLR signaling mediating excessive inflammatory responses. The aim of this study was to assess the role of GSK3-β activity in chronic intestinal inflammation.


METHODS
Chronic colitis was induced by dextran sodium sulfate (DSS) treatment. Mice were treated intraperitoneally with phosphate-buffered saline (PBS), CpG-ODN, or GSK3-β inhibitors (SB216763, LiCl). Intestinal inflammation was evaluated by histologic analysis and cytokine secretion of mesenteric lymph node cells (MLC). Nuclear extracts of MLC and lamina propria mononuclear cells (LPMC) were analyzed for nuclear factor kappaB (NF-κB) and CREB activity. Murine and human intestinal immune cells were stimulated in vitro with CpG-ODN, lipopolysaccharide (LPS), or anti-CD3 with or without LiCl.


RESULTS
GSK3-β blockade significantly reduced chronic intestinal inflammation and even abolished the colitis-intensifying effects of CpG-ODN treatment. In vitro inhibition of GSK3-β reduced the proinflammatory phenotype of both murine and human intestinal immune cells from chronic inflamed tissue. In vivo blockade of GSK3-β resulted in a shift from NF-κB activity toward CREB activity in murine MLC and LPMC.


CONCLUSIONS
Blockade of GSK3-β attenuates excessive proinflammatory TLR-mediated immune responses. GSK3-β inhibition therefore constitutes a promising therapeutic option for selectively reducing exaggerated intestinal immune reactions toward the luminal flora in inflammatory bowel disease.
Hofmann
Claudia
C
Department of Internal Medicine I, Regensburg University Medical Center, Germany. claudia.hofmann@klinik.uni-regensburg.de
Dunger
Nadja
N
Schölmerich
Jürgen
J
Falk
Werner
W
Obermeier
Florian
F
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000818:Animals; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000276:immunology / Q000494:pharmacology; D007422:Intestines / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009092:Mucous Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000032:analysis / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D017252:CD3 Complex; C408982:CPG-oligonucleotide; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; C417521:SB 216763; D051193:Toll-Like Receptors; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride