TY - JOUR
T1 - Anti-inflammatory effects of 8-hydroxy-2′-deoxyguanosine on lipopolysaccharide-induced inflammation via Rac suppression in Balb/c mice
AU - Choi, Seongwon
AU - Choi, Hyun Ho
AU - Lee, Sun Hye
AU - Ko, Seong Hee
AU - You, Ho Jin
AU - Ye, Sang Kyu
AU - Chung, Myung Hee
N1 - Funding Information:
The authors thank Byung-Hak Yoon for the cytokine analysis and Jin-Sook Ahn for her advice regarding the tissue staining. This work was supported by grants from the Korean Ministry of Science & Technology (Grant 2006-02293) and from the Seoul National University Hospital Research Fund (Grant 800-20060229).
PY - 2007/12/15
Y1 - 2007/12/15
N2 - Recently, we observed that 8-hydroxyguanosine triphosphate and 8-hydroxy-2′-deoxyguanosine (oh8dG) inactivate Rac and consequently down-regulate the Rac-linked NADPH oxidase, iNOS, and Cox2. Based on these observations, we tested whether oh8dG 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-α, IL-6, IL-18, and IL-12p70) in serum and infiltration of neutrophils, increased translocation of NF-κB p50 from the cytosol to the nucleus, and phosphorylation of c-Jun in lung tissues. Mice were pretreated with oh8dG (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 oh8dG were statistically significant. At the same time, oh8dG pretreatment inactivated Rac in lung tissues. Oh8dG pretreatment (50 mg/kg, ip) also significantly protected against LPS-induced septic death. Furthermore, oh8dG was more effective than acetyl salicylic acid in inhibiting these inflammatory responses. 8-Hydroxyguanosine also had some effect but was much weaker than oh8dG. The effects of normal nucleosides (dG, G, and A) were negligible or not significant. These results support an anti-inflammatory activity for oh8dG, which could be ascribed to its Rac-inactivating action.
AB - Recently, we observed that 8-hydroxyguanosine triphosphate and 8-hydroxy-2′-deoxyguanosine (oh8dG) inactivate Rac and consequently down-regulate the Rac-linked NADPH oxidase, iNOS, and Cox2. Based on these observations, we tested whether oh8dG 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-α, IL-6, IL-18, and IL-12p70) in serum and infiltration of neutrophils, increased translocation of NF-κB p50 from the cytosol to the nucleus, and phosphorylation of c-Jun in lung tissues. Mice were pretreated with oh8dG (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 oh8dG were statistically significant. At the same time, oh8dG pretreatment inactivated Rac in lung tissues. Oh8dG pretreatment (50 mg/kg, ip) also significantly protected against LPS-induced septic death. Furthermore, oh8dG was more effective than acetyl salicylic acid in inhibiting these inflammatory responses. 8-Hydroxyguanosine also had some effect but was much weaker than oh8dG. The effects of normal nucleosides (dG, G, and A) were negligible or not significant. These results support an anti-inflammatory activity for oh8dG, which could be ascribed to its Rac-inactivating action.
KW - 8-Hydroxy-2′-deoxyguanosine
KW - Acetyl salicylic acid
KW - Free radicals
KW - Inflammation
KW - Lipopolysaccharide
KW - Rac
KW - Reactive oxygen species
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U2 - 10.1016/j.freeradbiomed.2007.08.022
DO - 10.1016/j.freeradbiomed.2007.08.022
M3 - Article
C2 - 18037125
AN - SCOPUS:36248929864
SN - 0891-5849
VL - 43
SP - 1594
EP - 1603
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 12
ER -