Inhibition of Nuclear Factor κB by Phenolic Antioxidants: Interplay between Antioxidant Signaling and Inflammatory Cytokine Expression

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Abstract
Phenolic antioxidants inhibit the induction of inflammatory cytokines by inflammatory stimuli. Here, we analyzed the mechanism by which the antioxidants inhibit LPS-induced expression of tumor necrosis factor α (TNFα) in macrophages. Hydroquinone and tert-butyl hydroquinone, prototypes of phenolic antioxidants, block lipopolysaccharide (LPS)-induced transcription of TNFα and a nuclear factor (NF)-κB–mediated reporter gene expression, suggesting NF-κB as a target in the inhibition. Analyses of the NF-κB activation pathway revealed that the antioxidants do not inhibit LPS-induced activation of the IκB kinase activity, degradation of IκBα, or translocation of activated NF-κB into the nucleus, but they do block the formation of NF-κB/DNA binding complexes. In vitro experiments showed that the antioxidants do not directly interfere with DNA binding of NF-κB. Structure-activity analyses suggest that inhibition of NF-κB function involves the redox cycling property of the antioxidants. These findings implicate a redox-sensitive factor important for the binding of NF-κB to its DNA recognition sequence as a target molecule in the inhibition of NF-κB function and inflammatory cytokine expression by phenolic antioxidants.