Hofmann, Claudia and Dunger, Nadja and Schoelmerich, Juergen and Falk, Werner and Obermeier, Florian (2010) Glycogen Synthase Kinase 3-beta: A Master Regulator of Toll-like Receptor-mediated Chronic Intestinal Inflammation. INFLAMMATORY BOWEL DISEASES, 16 (11). pp. 1850-1858. ISSN 1078-0998,
Full text not available from this repository. (Request a copy)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 (GSK3-beta) 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-beta 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-beta 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-kappa B) 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-beta blockade significantly reduced chronic intestinal inflammation and even abolished the colitis-intensifying effects of CpG-ODN treatment. In vitro inhibition of GSK3-beta reduced the proinflammatory phenotype of both murine and human intestinal immune cells from chronic inflamed tissue. In vivo blockade of GSK3-beta resulted in a shift from NF-kappa B activity toward CREB activity in murine MLC and LPMC. Conclusions: Blockade of GSK3-beta attenuates excessive proinflammatory TLR-mediated immune responses. GSK3-beta inhibition therefore constitutes a promising therapeutic option for selectively reducing exaggerated intestinal immune reactions toward the luminal flora in inflammatory bowel disease.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EXPERIMENTAL COLITIS; BACTERIAL-DNA; INTERFERON-GAMMA; CPG MOTIFS; KAPPA-B; SIGNALING PATHWAYS; DENDRITIC CELLS; MONOCYTIC CELLS; BOWEL-DISEASE; MICE; GSK3-beta; TLR; experimental colitis; intestinal inflammation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Jul 2020 08:36 |
| Last Modified: | 07 Jul 2020 08:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/23945 |
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