The inhibition of NF-kappa B activation pathways and the induction of apoptosis by dithiocarbamates in T cells are blocked by the glutathione precursor N-acetyl-L-cysteine

Nuclear factor-kappa B regulates genes that control immune and inflammatory responses and are involved in the pathogenesis of several diseases, includ ing AIDS and cancer. It has been proposed that reactive oxygen intermediate s participate in NF-kappa B activation pathways, and compounds with putativ e antioxidant activity such as N-acetyl-L-cysteine (NAC) and pyrrolidine di thiocarbamate (PDTC) have been used interchangeably to demonstrate this poi nt. We examined their effects, separately and combined, on different stages of the NF-kappa B activation pathway, in primary and in transformed T cell s. We show that MAC, contrary to its reported role as an NF-kappa B inhibit or, can actually enhance rather than inhibit I kappa B degradation and, mos t importantly, show that in all cases NAC exerts a dominant antagonistic ef fect on PDTC-mediated NF-kappa B inhibition. This was observed at the level of I kappa B degradation, NF-kappa B DNA binding, and HIV-LTR-driven repor ter gene expression. NAC also counteracted growth arrest and apoptosis indu ced by dithiocarbamates. Antagonistic effects were further observed at the level of jun-NH2-terminal kinase, p38 and ATF-2 activation. Our findings ar gue against the widely accepted assumption that NAC inhibits all NF-kappa B activation pathways and shows that two compounds, previously thought to fu nction through a common inhibitory mechanism, can also have antagonistic ef fects.