MODULATION OF TRANSCRIPTION FACTOR NF-KAPPA-B ACTIVITY BY INTRACELLULAR GLUTATHIONE LEVELS AND BY VARIATIONS OF THE EXTRACELLULAR CYSTEINE SUPPLY

HIV-infected individuals and SIV-infected rhesus macaques have, on the average, decreased plasma cysteine and cystine concentrations and dec reased intracellular glutathione levels. We now show that a depletion of intracellular glutathione in a human T cell line (Molt-4) inhibits the activation and nuclear translocation of the transcription factor N F kappa B, whereas incubation with increasing extracellular concentrat ions of cysteine inhibits the DNA-binding and transactivating activity of NF kappa B. Because inhibition of DNA-binding activity is associat ed with increasing intracellular glutathione disulfide levels and GSSG can be shown to inhibit the DNA-binding activity directly in cell-fre e systems, our studies suggest that GSSG is a physiologically relevant inhibitor in intact cells also, NF kappa B controls many immunologica lly important genes, so our studies suggest that the immune system may be sensitive not only against a cysteine and glutathione deficiency b ut also against an excess of cysteine.