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

intercellular adhesion molecule-1; microglia; reactive oxygen species; STAT3 transcription factor; Toll-like receptor 4; 8-hydroxydeoxyguanosine

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
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