Anti-inflammatory effects of 8-hydroxydeoxyguanosine in LPS-induced microglia activation: suppression of STAT3-mediated intercellular adhesion molecule-1 expression.
To elucidate the roles of 8-hydroxydeoxyguanosine (oh(8)dG), the nucleoside of 8-hydroxyguanine (oh(8)Gua), we examined the effects of oh(8)dG upon LPS-induced intercellular adhesion molecule-1 (ICAM-1) expression and the underlying mechanisms in brain microglial cells. We found that oh(8)dG reduces LPS-induced reactive oxygen species (ROS) production, STAT3 activation, and ICAM-1 expression. oh(8)dG 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 oh(8)dG 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. Oh(8)dG 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, oh(8)dG in the cytosol probably functions as an anti-inflammatory molecule and should be considered as a candidate for development of anti-inflammatory agents.
Kim
Dong Hyun
DH
Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Cho
Ik Hyun
IH
Kim
Hong Sook
HS
Jung
Joo Eun
JE
Kim
Ja Eun
JE
Lee
Kwang Ho
KH
Park
Taekyu
T
Yang
Young Mok
YM
Seong
Seung-Yong
SY
Ye
Sang-Kyu
SK
Chung
Myung-Hee
MH
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004660:Encephalitis / Q000188:drug therapy; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018799:Intercellular Adhesion Molecule-1; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine