8-hydroxydeoxyguanosine suppresses NO production and COX-2 activity via Rac1/STATs signaling in LPS-induced brain microglia.
Free 8-hydroxydeoxyguanosine (oh(8)dG), a nucleoside of 8-hydroxyguanine (oh(8)Gua), present in cytosol is not incorporated into DNA. However, nothing is known about its biological function when it presents in cytosol as a free form. We demonstrate here for the first time that oh(8)dG inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production and cyclooxygenase-2 (COX-2) activity, and both gene transcriptions in microglia. Furthermore, oh(8)dG reduced mRNA levels of pro-inflammatory cytokine, such as IL-1beta, IL-6, and TNF-alpha, in activated BV2 cells. We also found that oh(8)dG suppressed reactive oxygen species (ROS) production through reduction of NADPH oxidase activity and blocked Rac1/STATs signal cascade. Finally, oh(8)dG suppressed recruitment of STATs and p300 to the iNOS and COX-2 promoters, and inhibited H3 histone acetylation. Taken together, these results provide new aspects of oh(8)dG as an anti-inflammatory agent.
Kim
Hong Sook
HS
Department of Pharmacology, Seoul National University College of Medicine, Chungno-gu, Seoul 110-799, Korea.
Ye
Sang-Kyu
SK
Cho
Ik Hyun
IH
Jung
Joo Eun
JE
Kim
Dong-Hyun
DH
Choi
Seongwon
S
Kim
Yong-Sik
YS
Park
Chung-Gyu
CG
Kim
Tae-Yoon
TY
Lee
Jung Weon
JW
Chung
Myung-Hee
MH
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009573:Nitrites; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050791:STAT Transcription Factors; D009569:Nitric Oxide; D000080242:8-Hydroxy-2'-Deoxyguanosine; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D020830:rac1 GTP-Binding Protein; D003849:Deoxyguanosine