The Suppression of T Cell Function and NFκB Expression by Serine Protease Inhibitors Is Blocked byN-Acetylcysteine

Breithaupt, Thomas B.; Vázquez, Abraham; Báez, Ineavely; Eylar, E. H.

doi:10.1006/cimm.1996.0258

Cited by 25 publications

(20 citation statements)

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“…39 NF-kB is a pivotal component of T-cell activation 14,16 and our finding that NAC can prevent NF-kB inhibition by TPCK therefore helps to explain this event. As mentioned earlier, however, TPCK can inhibit cellular signalling pathways at different levels and the immunosuppressive activity of TPCK is unlikely to be restricted solely to the NF-kB pathway.…”

Section: Discussionmentioning

confidence: 88%

“…6,10,22,27,39,63,64 Guesdon et al, 29 however, reported that TPCK blocked phosphorylation mechanisms, but found no evidence for protease involvement in IkBa degradation. Our finding that NAC, D-and L-cysteine block the effects of TPCK at the level of IkB phosphorylation is in line with these observations and suggests that TPCK interferes with NF-kB activation by modifying sulphydryl groups of proteins that regulate the IkB phosphorylation pathways.…”

Section: Discussionmentioning

confidence: 99%

“…TPCK has been shown to inhibit the induction of NF-kB activation in T-cells, 30,39 but the effects on constitutive NF-kB activity in T-cells has not yet been monitored. Considering the potential role of NF-kB in the regulation of proliferation and apoptosis, we monitored the effects of both TPCK and NAC on different steps in the NF-kB activation pathway in transformed T-cells.…”

Section: Effects Of Tpck and Nac On Ikb Phosphorylation In Tpi T-cellsmentioning

confidence: 99%

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N-acetylcysteine blocks apoptosis induced by N-α-tosyl-L-phenylalanine chloromethyl ketone in transformed T-cells

et al. 1999

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The serine protease inhibitor N-a-tosyl-L-phenylalanine chloromethyl ketone (TPCK) can interfere with cell-cycle progression and has also been shown either to protect cells from apoptosis or to induce apoptosis. We tested the effect of TPCK on two transformed T-cell lines. Both Jurkat T-cells and Theileria parva-transformed T-cells were shown to be highly sensitive to TPCK-induced growth arrest and apoptosis. Surprisingly, we found that the thiol antioxidant, Nacetylcysteine (NAC), as well as L-or D-cysteine blocked TPCK-induced growth arrest and apoptosis. TPCK inhibited constitutive NF-kB activation in T. parva-transformed T-cells, with phosphorylation of IkBa and IkBb being inhibited with different kinetics. TPCK-mediated inhibition of IkB phosphorylation, NF-kB DNA binding and transcriptional activity were also prevented by NAC or cysteine. Our observations indicate that apoptosis and NF-kB inhibition induced by TPCK result from modifications of sulphydryl groups on proteins involved in regulating cell survival and the NF-kB activation pathway(s).

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Tpck and Nac On Ikb Phosphorylation In Tpi T-cellsmentioning

confidence: 99%

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N-acetylcysteine blocks apoptosis induced by N-α-tosyl-L-phenylalanine chloromethyl ketone in transformed T-cells

et al. 1999

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“…RAW 264.7 were pretreated with TPCK for 1 h after which they were stimulated with RANKL for 8 h. Control cells were not treated with TPCK. TPCK is a selective, irreversible inhibitor of (30,31) RT-PCR analysis from unstimulated and stimulated cells is shown in Fig. 6.…”

Section: Rankl-induced Up-regulation Of C-myc Requires Traf6mentioning

confidence: 99%

c-myc Is Required for Osteoclast Differentiation

Battaglino¹,

D²,

Fu³

et al. 2002

Journal of Bone and Mineral Research

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The role of the receptor activator of nuclear factor B (NF-B) ligand (RANKL)-a tumor necrosis factor (TNF)-related cytokine-in osteoclast formation has been established clearly. However, the downstream signaling pathways activated by this cytokine remain largely unknown. To identify genes that play a role in osteoclastogenesis, we used RAW 264.7 mouse monocytes as a model system for the differentiation of multinucleated osteoclasts from mononucleated precursors. RAW 264.7 cells were induced with RANKL to form multinucleated giant osteoclast-like cells (OCLs) that expressed a number of osteoclast-specific markers and were able to form resorption pits on both calcium phosphate films and bone slices. This system was used to identify genes that are regulated by RANKL and may play a role in osteoclast differentiation.

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“…However, these inhibitors have also been shown exhibit other biochemical effects on cells. Specifically, TLCK and TPCK have been shown to block activation of NFκB [35], prevent the activation of pp70(s6k), a mitogenrelated kinase [36], and to suppress the processing of caspases in some model systems [37,38]. In contrast, these two proteases have been shown to both induce and enhance cell death upon treatment with various cytotoxic agents [39][40][41].…”

Section: Caspase Independent Dna Degradationmentioning

confidence: 99%

An endogenous calcium-dependent, caspase-independent intranuclear degradation pathway in thymocyte nuclei: Antagonism by physiological concentrations of K+ ions

Ajiro

Bortner

Westmoreland

et al. 2008

Experimental Cell Research

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Calcium ions have been implicated in apoptosis for many years, however the precise role of this ion in the cell death process remains incomplete. We have extensively examined the role of Ca 2+ on nuclear degradation in vitro using highly purified nuclei isolated from non-apoptotic rat thymocytes. We show that these nuclei are devoid of CAD (caspase-activated DNase), and DNA degradation occurs independent of caspase activity. Serine proteases rather than caspase-3 appear necessary for this Ca 2+ -dependent DNA degradation in nuclei. We analyzed nuclei treated with various concentrations of Ca 2+ in the presence of both a physiological (140 mM) and apoptotic (40 mM) concentration of KCl. Our results show that a 5-fold increase in Ca 2+ is required to induce DNA degradation at the physiological KCl concentration compared to the lower, apoptotic concentration of the cation. Ca 2+ -induced internucleosomal DNA degradation was also accompanied by the release of histones, however the apoptotic-specific phosphorylation of histone H2B does not occur in these isolated nuclei. Interestingly, physiological concentrations of K + inhibit both Ca 2+ -dependent DNA degradation and histone release suggesting a reduction of intracellular K + is necessary for this apoptosis-associated nuclear degradation in cells. Together, these data define an inherent caspaseindependent catabolic pathway in thymocyte nuclei that is sensitive to physiological concentrations of interacellular cations.

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The Suppression of T Cell Function and NFκB Expression by Serine Protease Inhibitors Is Blocked byN-Acetylcysteine

Cited by 25 publications

References 0 publications

N-acetylcysteine blocks apoptosis induced by N-α-tosyl-L-phenylalanine chloromethyl ketone in transformed T-cells

N-acetylcysteine blocks apoptosis induced by N-α-tosyl-L-phenylalanine chloromethyl ketone in transformed T-cells

c-myc Is Required for Osteoclast Differentiation

An endogenous calcium-dependent, caspase-independent intranuclear degradation pathway in thymocyte nuclei: Antagonism by physiological concentrations of K+ ions

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