title: The inhibition of NF-kappaB activation pathways and the induction of apoptosis by dithiocarbamates in T cells are blocked by the glutathione precursor N-acetyl-L-cysteine.
abstract: Nuclear factor-kappaB regulates genes that control immune and inflammatory responses and are involved in the pathogenesis of several diseases, including AIDS and cancer. It has been proposed that reactive oxygen intermediates participate in NF-kappaB activation pathways, and compounds with putative antioxidant activity such as N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) have been used interchangeably to demonstrate this point. We examined their effects, separately and combined, on different stages of the NF-kappaB activation pathway, in primary and in transformed T cells. We show that NAC, contrary to its reported role as an NF-kappaB inhibitor, can actually enhance rather than inhibit IkappaB degradation and, most importantly, show that in all cases NAC exerts a dominant antagonistic effect on PDTC-mediated NF-kappaB inhibition. This was observed at the level of IkappaB degradation, NF-kappaB DNA binding, and HIV-LTR-driven reporter gene expression. NAC also counteracted growth arrest and apoptosis induced by dithiocarbamates. Antagonistic effects were further observed at the level of jun-NH2-terminal kinase, p38 and ATF-2 activation. Our findings argue against the widely accepted assumption that NAC inhibits all NF-kappaB activation pathways and shows that two compounds, previously thought to function through a common inhibitory mechanism, can also have antagonistic effects.
authors.affiliation: Laboratory of Molecular Pathology, Institute of Animal Pathology, University of Berne, Switzerland.
authors.forename: P C
authors.initials: PC
authors.lastname: Fernandez
authors.forename: J
authors.initials: J
authors.lastname: Machado
authors.forename: V T
authors.initials: VT
authors.lastname: Heussler
authors.forename: C
authors.initials: C
authors.lastname: Botteron
authors.forename: G H
authors.initials: GH
authors.lastname: Palmer
authors.forename: D A
authors.initials: DA
authors.lastname: Dobbelaere
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D051698:Activating Transcription Factor 2; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D004221:Disulfiram / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013859:Thiocarbamates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D014157:Transcription Factors; C020972:pyrrolidine dithiocarbamic acid; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D004221:Disulfiram; D000111:Acetylcysteine