Anti-inflammatory effects of 8-hydroxy-2'-deoxyguanosine on lipopolysaccharide-induced inflammation via Rac suppression in Balb/c mice.
Recently, we observed that 8-hydroxyguanosine triphosphate and 8-hydroxy-2'-deoxyguanosine (oh(8)dG) inactivate Rac and consequently down-regulate the Rac-linked NADPH oxidase, iNOS, and Cox2. Based on these observations, we tested whether oh(8)dG has anti-inflammatory activity in vivo in lipopolysaccharide (LPS)-treated mice. LPS (1 mg/kg, ip)-treated mice exhibit marked inflammatory responses, including increases in proinflammatory cytokines (TNF-alpha, IL-6, IL-18, and IL-12p70) in serum and infiltration of neutrophils, increased translocation of NF-kappaB p50 from the cytosol to the nucleus, and phosphorylation of c-Jun in lung tissues. Mice were pretreated with oh(8)dG (up to 60 mg/kg, ip) 4 h before LPS injection, and this pretreatment dose-dependently inhibited the inflammatory responses; the inhibitions observed with 60 mg/kg oh(8)dG were statistically significant. At the same time, oh(8)dG pretreatment inactivated Rac in lung tissues. Oh(8)dG pretreatment (50 mg/kg, ip) also significantly protected against LPS-induced septic death. Furthermore, oh(8)dG was more effective than acetyl salicylic acid in inhibiting these inflammatory responses. 8-Hydroxyguanosine also had some effect but was much weaker than oh(8)dG. The effects of normal nucleosides (dG, G, and A) were negligible or not significant. These results support an anti-inflammatory activity for oh(8)dG, which could be ascribed to its Rac-inactivating action.
Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Seongwon
S
Choi
Hyun-Ho
HH
Choi
Sun-Hye
SH
Lee
Seong-Hee
SH
Ko
Ho-Jin
HJ
You
Sang-Kyu
SK
Ye
Myung-Hee
MH
Chung
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D005609:Free Radicals; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D000080242:8-Hydroxy-2'-Deoxyguanosine; D009195:Peroxidase; D048031:JNK Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D003849:Deoxyguanosine