Abstract | 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: 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.
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Authors | Claudia Hofmann, Nadja Dunger, Jürgen Schölmerich, Werner Falk, Florian Obermeier |
Journal | Inflammatory bowel diseases
(Inflamm Bowel Dis)
Vol. 16
Issue 11
Pg. 1850-8
(Nov 2010)
ISSN: 1536-4844 [Electronic] England |
PMID | 20848477
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adjuvants, Immunologic
- CD3 Complex
- CPG-oligonucleotide
- Cyclic AMP Response Element-Binding Protein
- Cytokines
- Indoles
- Lipopolysaccharides
- Maleimides
- NF-kappa B
- Oligodeoxyribonucleotides
- SB 216763
- Toll-Like Receptors
- Glycogen Synthase Kinase 3 beta
- Glycogen Synthase Kinase 3
- Lithium Chloride
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Topics |
- Adjuvants, Immunologic
(pharmacology)
- Adult
- Aged
- Animals
- CD3 Complex
(immunology, metabolism)
- Cells, Cultured
- Chronic Disease
- Colitis
(chemically induced, drug therapy, enzymology, immunology, pathology)
- Cyclic AMP Response Element-Binding Protein
(analysis, immunology)
- Cytokines
(immunology, metabolism)
- Female
- Glycogen Synthase Kinase 3
(antagonists & inhibitors, immunology, metabolism)
- Glycogen Synthase Kinase 3 beta
- Humans
- Indoles
(immunology, pharmacology)
- Intestines
(enzymology, immunology, pathology)
- Lipopolysaccharides
(administration & dosage, immunology, metabolism)
- Lithium Chloride
(pharmacology)
- Lymph Nodes
(drug effects, immunology, metabolism)
- Male
- Maleimides
(immunology, pharmacology)
- Mice
- Mice, Inbred BALB C
- Middle Aged
- Mucous Membrane
(drug effects, immunology, metabolism)
- NF-kappa B
(analysis, immunology)
- Oligodeoxyribonucleotides
(immunology, pharmacology)
- Toll-Like Receptors
(immunology, metabolism)
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