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

Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health/Centers for Disease Control and Prevention, Morgantown, West Virginia (Q.M., K.K., B.J.C.); Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana (J.Y.)

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

Received November 6, 2002; accepted April 24, 2003.

Address correspondence to: Qiang Ma, CDC/NIOSH, Mailstop 3014, 1095 Willowdale Rd., Morgantown, WV 26505. E-mail: qam1{at}cdc.gov

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