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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.
Biol Chem. 1999 Dec; 380(12):1383-94.BC

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+Show Affiliations

Laboratory of Molecular Pathology, Institute of Animal Pathology, University of Berne, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

10661865

Citation

Fernandez, P C., et al. "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." Biological Chemistry, vol. 380, no. 12, 1999, pp. 1383-94.
Fernandez PC, Machado J, Heussler VT, et al. 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. Biol Chem. 1999;380(12):1383-94.
Fernandez, P. C., Machado, J., Heussler, V. T., Botteron, C., Palmer, G. H., & Dobbelaere, D. A. (1999). 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. Biological Chemistry, 380(12), 1383-94.
Fernandez PC, et al. 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. Biol Chem. 1999;380(12):1383-94. PubMed PMID: 10661865.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Fernandez,P C, AU - Machado,J,Jr AU - Heussler,V T, AU - Botteron,C, AU - Palmer,G H, AU - Dobbelaere,D A, PY - 2000/2/8/pubmed PY - 2000/3/11/medline PY - 2000/2/8/entrez SP - 1383 EP - 94 JF - Biological chemistry JO - Biol Chem VL - 380 IS - 12 N2 - 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. SN - 1431-6730 UR - https://www.unboundmedicine.com/medline/citation/10661865/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_ L2 - https://www.degruyter.com/document/doi/10.1515/BC.1999.178 DB - PRIME DP - Unbound Medicine ER -