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
Pc. Fernandez et al., 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, BIOL CHEM, 380(12), 1999, pp. 1383-1394
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.