The Inhibition of NF-B 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-κB 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-κB 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-κB activation pathway, in primary and in transformed T cells. We show that NAC, contrary to its reported role as an NF-κB inhibitor, can actually enhance rather than inhibit IκB degradation and, most importantly, show that in all cases NAC exerts a dominant antagonistic effect on PDTC-mediated NF-κB inhibition. This was observed at the level of IκB degradation, NF-κB 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-$ NH_{2} $-terminal kinase, p38 and ATF-2 activation. Our findings argue against the widely accepted assumption that NAC inhibits all NF-κB activation pathways and shows that two compounds, previously thought to function through a common inhibitory mechanism, can also have antagonistic effects..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
1999 |
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| Erschienen: |
1999 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:380 |
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| Enthalten in: |
Biological Chemistry - 380(1999), 12 vom: 20. Dez., Seite 1383-1394 |
| Beteiligte Personen: |
Fernandez, Paula C. [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Anmerkungen: |
© © 1999 by Walter de Gruyter GmbH & Co. KG |
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| doi: |
10.1515/BC.1999.178 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
GRUY004163362 |
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| 100 | 1 | |a Fernandez, Paula C. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a The Inhibition of NF-B Activation Pathways and the Induction of Apoptosis by Dithiocarbamates in T Cells Are Blocked by the Glutathione Precursor N-Acetyl-L-Cysteine |
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| 500 | |a © © 1999 by Walter de Gruyter GmbH & Co. KG | ||
| 520 | |a Abstract Nuclear factor-κB 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-κB 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-κB activation pathway, in primary and in transformed T cells. We show that NAC, contrary to its reported role as an NF-κB inhibitor, can actually enhance rather than inhibit IκB degradation and, most importantly, show that in all cases NAC exerts a dominant antagonistic effect on PDTC-mediated NF-κB inhibition. This was observed at the level of IκB degradation, NF-κB 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-$ NH_{2} $-terminal kinase, p38 and ATF-2 activation. Our findings argue against the widely accepted assumption that NAC inhibits all NF-κB activation pathways and shows that two compounds, previously thought to function through a common inhibitory mechanism, can also have antagonistic effects. | ||
| 700 | 1 | |a Machado, Joel |4 aut | |
| 700 | 1 | |a Heussler, Volker T. |4 aut | |
| 700 | 1 | |a Botteron, Catherine |4 aut | |
| 700 | 1 | |a Palmer, Guy H. |4 aut | |
| 700 | 1 | |a Dobbelaere, Dirk A.E. |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biological Chemistry |d Walter de Gruyter |g 380(1999), 12 vom: 20. Dez., Seite 1383-1394 |w (DE-627)GRUY000408883 |7 nnns |
| 773 | 1 | 8 | |g volume:380 |g year:1999 |g number:12 |g day:20 |g month:12 |g pages:1383-1394 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1515/BC.1999.178 |z lizenzpflichtig |3 Volltext |
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