Stimulation of free radical generation in human leukocytes by various agents including tumor necrosis factor is a calmodulin dependent process

Das, Undurti N.; Maruvada, Padma; Sagar, P.; Ramesh, G.; Koratkar, Revati

doi:10.1016/0006-291x(90)90626-x

Cited by 109 publications

(34 citation statements)

References 13 publications

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“…The NF-~cB activation process requires the release of I~B from the cytoplasmic complex [23]. In our experiments, TNF-a which induces the production of free radicals [24][25][26] as well as H202 led to NF-~B activation, iNOS gene expression, and NO release in VSMC. Reactive oxygen species may modulate the cellular redox state, which has been linked to NF-~B activation [27].…”

Section: Discussionsupporting

confidence: 47%

Neopterin activates transcription factor nuclear factor‐κB in vascular smooth muscle cells

et al. 1996

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We have previously shown that the pteridine compound neopterin stimulates inducible nitric oxide synthase (iNOS) gene expression in vascular smooth muscle cells in vitro. The mechanisms whereby neopterin exhibits these effects remained unclear. The present study demonstrates that neopterin induces the translocation of the transcription factor nuclear factor-w~B (NF-~B) to the nucleus. Pretreatment of cells with the antioxidant pyrrolidine dithiocarbamate completely suppressed the effects of neopterin on NF-r,~B activation, iNOS gene expression, and nitric oxide release. From these data we conclude that neopterin activates the translocation of NF-r,B suhunits to the nucleus by modulating the intracellular redox state. This is one possible explanation for the impact of neopterin on iNOS gene expression.

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Section: Discussionsupporting

confidence: 47%

Neopterin activates transcription factor nuclear factor‐κB in vascular smooth muscle cells

et al. 1996

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“…However, the involvement of PKA in TNFa-induced protein phosphorylation has yet to be demonstrated (Pfeilschifter et al, 1991). Calmodulin has also been implicated in the action of TNFo since free radical generation induced by this cytokine in human leukocytes is inhibited by calmodulin antagonists (Das et al, 1990).…”

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confidence: 99%

Growth arrest of the breast cancer cell line, T47D, by TNF α; cell cycle specificity and signal transduction

Pusztai

Lewis²,

McGee³

1993

Br J Cancer

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SummaryThe effects of tumour necrosis factor-a (TNFa) on the growth and DNA synthesis of the human breast cell line, T47D, were studied. A dose-dependent, reversible inhibition of thymidine incorporation and cell growth was observed in the range of 0.1 ng ml-I to 100 ng ml-of TNFa. Cell viability was not impaired in any of the experiments. Flow-cytometric DNA analysis demonstrated that after 24 h exposure to TNFa, T47D cells accumulated in the GI phase of the cell cycle, and were depleted in the G2/M and S phases, suggesting a block in the progression of the GI/S transition. The involvement of protein kinases (PK) and protein phosphatases in TNFa-induced signal transduction was also investigated. A transient and rapid 2-fold increase in total cellular protein kinase C (PKC) activity was detected after 10min exposure to TNFa. To study the role of the observed PKC activation in the cytostatic effect of TNFa, T47D cells were exposed to the cytokine in the presence of the potent PKC inhibitor, H7. The inhibitory effect of TNFa on thymidine incorporation was not affected by exposure to H7 at concentrations sufficient to block the stimulation of thymidine up-take induced by the PKC agonist, phorbol-12-myristate-13-acetate (PMA). The involvement of other signalling pathways was addressed using the cyclic nucleotide-dependent PK inhibitor, H8; the calmodulin-dependent PK inhibitor, W7; and the inhibitor of protein phosphatases PPI and PP2B, okadaic acid. Exposure of T47D cells to these enzyme inhibitors failed to antagonise the inhibition of thymidine incorporation by TNFa. Taken together, these results indicate that the cytostatic effect of TNFa on T47D cells occurs at the GI/S transition of the cell cycle, and is mediated by an intracellular pathway which does not involve the activity of protein kinases C and A, nor protein phosphatases PP1, PP2B.

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“…ROS include superoxide radicals (O2"-/.O2H), hydrogen peroxide (H202), organic hydroperoxides, and hydroxyl radical (OH-). Eukaryotic cells produce ROS continuously as side products of the mitochondrial electron transfer chain reactions (31), but also upon exposure to different stimuli that can activate NF-KB, including UV light, hydrogen peroxide, and inflammatory cytokines, such as tumor necrosis factor t~ (TNFet) and interleukin 1 (18,19,43,64).…”

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confidence: 99%

Inhibition of I kappa B-alpha phosphorylation and degradation and subsequent NF-kappa B activation by glutathione peroxidase overexpression.

Kretz-Remy

Mehlen

Mirault

et al. 1996

The Journal of Cell Biology

251

134

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Abstract. We report here that both KB-dependent transactivation of a reporter gene and NF-KB activation in response to tumor necrosis factor (TNFc 0 or H202 treatments are deficient in human T47D cell transfectants that overexpress seleno-glutathione peroxidase (GSHPx). These cells feature low reactive oxygen species (ROS) levels and decreased intracellular ROS burst in response to TNFot treatment. Decreased ROS levels and NF-KB activation were likely to result from GSHPx increment since these phenomena were no longer observed when GSHPx activity was reduced by selenium depletion. The cellular contents of the two NF-KB subunits (p65 and p50) and of the inhibitory subunit IKB-a were unaffected by GSHPx overexpression, suggesting that increased GSHPx activity interfered with the activation, but not the synthesis or stability, of NF-KB. Nuclear translocation of NF-KB as well as IKB-ot degradation were inhibited in GSHPx-overexpressing cells exposed to oxidative stress. Moreover, in control T47D cells exposed to TNFa, a time correlation was observed between elevated ROS levels and IKB-ot degradation. We also show that, in growing T47D cells, GSHPx overexpression altered the isoform composition of IKB-et, leading to the accumulation of the more basic isoform of this protein. GSHPx overexpression also abolished the TNFe~-mediated transient accumulation of the acidic and highly phosphorylated IKB-et isoform. These results suggest that intracellular ROS are key elements that regulate the phosphorylation of IKB-~, a phenomenon that precedes and controls the degradation of this protein, and then NF-KB activation.T rtE transcription factor NF-KB plays a pivotal role in the regulation of a wide variety of cellular genes, particularly those involved in immune and inflammatory responses, and also participates in the regulation of viral promoters, including the human immunodeficiency virus long terminal repeat (HIV-1 LTR) (3,7,29,51,66). Five different subunits of NF-KB have been described that can homo-and heterodimerize (21, 53). These polypeptides belong to the rel family of transcription factors, and the more frequent and therefore prototypical form of NF-KB is a heterodimer complex containing the p50 and p65/RelA subunits (6,11,28,59,67). Unlike most transcription factors, these proteins reside in the cytoplasm in a latent form and must therefore translocate into the nucleus to function (5). In unstimulated cells, the nuclear import of the NF-KB DNA-binding dimer p65/RelAp50 is prevented by high-affinity association of the p65/ RelA subunit with a cytoplasmic inhibitor called IKB (4,13,57,71 family of distinct proteins (62) and interacts, through its ankyrin-like repeats, with the nuclear localization signals of p50 and p65/RelA (9, 34). The prototypical IKB protein involved in cytoplasmic retention of NF-KB dimers is IKB-a, encoded by the MAD-3 gene (32). The inactive NF-KB-IKB-ot complexes are dissociated in response to a variety of extracellular stimuli, thereby allowing free NF-KB dimers to translocate to the nucleus ...

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Stimulation of free radical generation in human leukocytes by various agents including tumor necrosis factor is a calmodulin dependent process

Cited by 109 publications

References 13 publications

Neopterin activates transcription factor nuclear factor‐κB in vascular smooth muscle cells

Neopterin activates transcription factor nuclear factor‐κB in vascular smooth muscle cells

Growth arrest of the breast cancer cell line, T47D, by TNF α; cell cycle specificity and signal transduction

Inhibition of I kappa B-alpha phosphorylation and degradation and subsequent NF-kappa B activation by glutathione peroxidase overexpression.

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