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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Selective inhibition of l kappaB alpha phosphorylation and HIV-1 LTR-directed gene expression by novel antioxidant compounds.

Oxidative stress activates the NF-kappaB/Rel transcription factors which are involved in the activation of numerous immunoregulatory genes and the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). In the present study, we examined the effects of established and novel compounds including antioxidants, ribonucleotide reductase inhibitors, and iron chelators on NF-kappaB activation and HIV LTR-mediated gene expression induced by TNF-alpha. N-Acetylcysteine (NAC), pyrrolidinedithiocarbamate (PDTC), and Trimidox (TD) at various concentrations inhibited TNF-alpha-induced NF-kappaB binding in Jurkat cells. Pretreatment of cells with these compounds prior to stimulation prevented I kappaB alpha degradation. Phosphorylation of I kappaB alpha, a prerequisite for its signal-induced degradation, was abrogated in these cells, indicating that oxidative stress is an essential step in the NF-kappaB activation pathway. On the other hand, iron chelators desferrioxamine, pyridoxal isonicotinoyl hydrazone (PIH), and salicylaldehyde isonicotinoyl hydrazone (SIH) showed no inhibition of TNF-alpha-induced NF-kappaB DNA-binding activity. Synergistic induction of HIV-1 LTR-mediated gene expression by TNF-alpha and the HIV-1 transactivator Tat in Jurkat cells was significantly suppressed in the presence of NAC and TD, but not PDTC. The inhibition of NAC and TD on LTR-directed gene expression was diminished when NF-kappaB-binding sites in the LTR were deleted, indicating that these compounds affected the NF-kappaB component of the synergism. Iron chelators PIH and SIH also showed some inhibitory effect on LTR-mediated gene activation, presumably through an NF-kappaB-independent mechanism. These experiments demonstrate that TD, at concentration 50 times lower than the effective concentration of NAC, potently inhibits NF-kappaB activity and suppresses HIV LTR expression.[1]

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