Anti-inflammatory effects of 8-hydroxydeoxyguanosine in LPS-induced microglia activation: suppression of STAT3-mediated intercellular adhesion molecule-1 expression.
- Author:
Dong Hyun KIM
1
;
Ik Hyun CHO
;
Hong Sook KIM
;
Joo Eun JUNG
;
Ja Eun KIM
;
Kwang Ho LEE
;
Taekyu PARK
;
Young Mok YANG
;
Seung Yong SEONG
;
Sang Kyu YE
;
Myung Hee CHUNG
Author Information
1. Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea. sangkyu@snu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
intercellular adhesion molecule-1;
microglia;
reactive oxygen species;
STAT3 transcription factor;
Toll-like receptor 4;
8-hydroxydeoxyguanosine
- MeSH:
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
- From:Experimental & Molecular Medicine
2006;38(4):417-427
- CountryRepublic of Korea
- Language:English
-
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.
