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 (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-α, IL-6 and IFN-γ. 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.