Exp Mol Med.
2006 Aug;38(4):417-427.
Anti-inflammatory effects of 8-hydroxydeoxyguanosine in LPS-induced microglia activation: suppression of STAT3-mediated intercellular adhesion molecule-1 expression
- Affiliations
-
- 1Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea. sangkyu@snu.ac.kr
- 2Department of Microbiology, Seoul National University College of Medicine, Seoul 110-799, Korea.
- 3Department of Physiology, College of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749, Korea.
- 4Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju 380-701, Korea.
- 5Department of Pathology, College of Medicine Bio-Food and Drug Research Center, Konkuk University, Chungju 380-701, Korea.
Abstract
- To elucidate the roles of 8-hydroxydeoxyguanosine (oh8dG), the nucleoside of 8-hydroxyguanine (oh8Gua), we examined the effects of oh8dG upon LPS-induced intercellular adhesion molecule-1 (ICAM-1) expression and the underlying mechanisms in brain microglial cells. We found that oh8dG reduces LPS-induced reactive oxygen species (ROS) production, STAT3 activation, and ICAM-1 expression. oh8dG also suppresses pro-inflammatory cytokines, such as TNF-alpha, IL-6 and IFN-gamma. Overexpression of dominant negative STAT3 completely diminshed STAT3-mediated ICAM-1 transcriptional activity. Chromatin immunoprecipitation studies revealed that oh8dG inhibited recruitment of STAT3 to the ICAM-1 promoter, followed by a decrease in ICAM-1 expression. Using mice lacking a functional Toll-like receptor 4 (TLR4), we demonstrated that, while TLR4+/+ microglia were activated by LPS, TLR4-/-microglia exhibited inactivated STAT3 in response to LPS. Evidently, LPS modulates STAT3-dependent ICAM-1 induction through TLR4-mdiated cellular responses. Oh8dG apparently plays a role in anti-inflammatory actions via suppression of ICAM-1 gene expression by blockade of the TLR4-STAT3 signal cascade in inflammation-enhanced brain microglia. Therefore, oh8dG in the cytosol probably functions as an anti-inflammatory molecule and should be considered as a candidate for development of anti-inflammatory agents.
Keyword
MeSH Terms
-
Toll-Like Receptor 4/genetics
STAT3 Transcription Factor/physiology
Reactive Oxygen Species/metabolism
Microglia/*drug effects/metabolism
Mice, Knockout
Mice, Inbred C57BL
Mice
Male
Lipopolysaccharides/*pharmacology
Intercellular Adhesion Molecule-1/*metabolism
Inflammation Mediators/metabolism
Encephalitis/drug therapy
Deoxyguanosine/*analogs & derivatives/pharmacology/therapeutic use
Cytokines/biosynthesis
Cell Survival/drug effects
Brain/cytology/drug effects
Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
Animals
- Full Text Links
-
- Actions
-
Cited
- CITED
-
- Close
- Share
-
- Similar articles
-
- HMGB1-Binding Heptamer Confers Anti-Inflammatory Effects in Primary Microglia Culture
- Epigallocatechin-3-gallate Inhibits the Expression of Adhesion Molecules by Blocking Nuclear Factor Kappa B Signaling in Intestinal Epithelial Cells
- Heparin Attenuates the Expression of TNF alpha-induced Cerebral Endothelial Cell Adhesion Molecule
- Baicalin alleviates lipopolysaccharide-induced neuroglial activation and inflammatory factors activation in hippocampus of adult mice
- The Anti-inflammatory Effect of Rosiglitazone on Renal Injury in Sepsis Model
