Inhibition of nuclear factor kappaB by phenolic antioxidants: interplay between antioxidant signaling and inflammatory cytokine expression.
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 alpha (TNFalpha) in macrophages. Hydroquinone and tert-butyl hydroquinone, prototypes of phenolic antioxidants, block lipopolysaccharide (LPS)-induced transcription of TNFalpha and a nuclear factor (NF)-kappaB-mediated reporter gene expression, suggesting NF-kappaB as a target in the inhibition. Analyses of the NF-kappaB activation pathway revealed that the antioxidants do not inhibit LPS-induced activation of the IkappaB kinase activity, degradation of IkappaBalpha, or translocation of activated NF-kappaB into the nucleus, but they do block the formation of NF-kappaB/DNA binding complexes. In vitro experiments showed that the antioxidants do not directly interfere with DNA binding of NF-kappaB. Structure-activity analyses suggest that inhibition of NF-kappaB function involves the redox cycling property of the antioxidants. These findings implicate a redox-sensitive factor important for the binding of NF-kappaB to its DNA recognition sequence as a target molecule in the inhibition of NF-kappaB function and inflammatory cytokine expression by phenolic antioxidants.
Ma
Qiang
Q
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, WV 26505, USA. qam1@cdc.gov
Kinneer
Krista
K
Ye
Jianping
J
Chen
Bruce J
BJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D010636:Phenols / Q000494:pharmacology*; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D010636:Phenols; D014409:Tumor Necrosis Factor-alpha; D004247:DNA