Activation of NF-κB by PM10 Occurs via an Iron-Mediated Mechanism in the Absence of IκB Degradation

Jiménez, Luis A.; Thompson, J.; Brown, Debbie; Rahman, Irfan; Antonicelli, Frank; Duffin, Rodger; Drost, Ellen; Hay, Ronald T.; Donaldson, Ken; MacNee, William

doi:10.1006/taap.2000.8957

Cited by 173 publications

(102 citation statements)

References 46 publications

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“…However, despite the evidence that R-roscovitine may directly inhibit NF-kB activation in some cancer cell lines we could find no evidence of this in resting or stimulated neutrophils. We performed dual experiments, IkBa Western blotting and confocal microscopy for labelled p65, because recent reports had suggested that NF-kB activation could occur independently of IkBa inhibition [28,34]. We also examined mRNA and protein levels of XIAP, an NF-kB-regulated survival protein.…”

Section: Discussionmentioning

confidence: 99%

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The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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Successful resolution of inflammation requires inflammatory cells such as neutrophils to undergo apoptosis prior to non-inflammatory phagocytosis by professional phagocytes. Recently, cyclin-dependent kinase (CDK) inhibitors (e.g. R-roscovitine) have been shown to induce neutrophil apoptosis and enhance the resolution of inflammation. Interestingly, NF-jB and MAPK pathways and key endogenous survival proteins (typified by Mcl-1) are involved in the regulation of neutrophil apoptosis and, in cancer-cell lines, have been implicated as possible targets of CDK inhibitors. Here, we demonstrate that R-roscovitine over-rides TNF-a and LPS-induced survival (determined by morphological examination and binding of fluorescently labelled annexin-V) of isolated peripheral blood neutrophils. This effect did not appear to be mediated via effects on early markers of neutrophil activation (e.g. surface marker expression, shape change, aggregation and superoxide anion generation), by direct inhibition of NF-jB activation (assessed by cytoplasmic IjBa proteolysis and NF-jB p65 subunit translocation) and ERK activation (determined by specific ERK phosphorylation) but due to down-regulation (at protein and mRNA level) of the survival protein Mcl-1 but not the pro-apoptotic bcl-2 homologue Bim. These findings suggest that key endogenous survival proteins may be the targets of CDK inhibitors and consequently may be of critical importance in the resolution of inflammation.

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Section: Discussionmentioning

confidence: 99%

“…2B). This method was utilized to ensure that NF-kB activation was not occurring independently of IkBa degradation as has been previously reported [28]. Neutrophils treated with R-roscovitine have a green cytoplasm and a red nucleus, an appearance that contra-indicates activation.…”

Section: R-roscovitine Does Not Affect P65 Translocation Stimulated Bmentioning

confidence: 99%

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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“…In addition, target cells, such as airway epithelial cells and macrophages, generate ROS in response to particle uptake by biologically catalysed oxidation reactions that occur in the cell membrane and mitochondria [4,[40][41][42]. In vitro studies have shown that inhaled PM causes expression of nuclear factor (NF)-kB-related genes and oxidant-dependent NF-kB activation [43,44]. The dose of bio-available transition metal, rather than particulate mass, may be the primary determinant of acute inflammatory response [35,37,44].…”

Section: Biological and Epidemiological Evidencementioning

confidence: 99%

“…At higher exposure, the transcription NF-kB and activator protein-1 responses would be activated. This would lead to NF-kB and mitogen-activated protein kinase signalling, altering the function of mitochondria or NADPH, and to increased expression of pro-inflammatory cytokines (such as TNF-a and IL-8 and IL-6) and genes coding adhesion molecules [2,6,15,43,44]. Any enhanced inflammatory response would lead to additional generation of ROS and RNS, together with oxidative DNA damage ( fig.…”

Section: Biological and Epidemiological Evidencementioning

confidence: 99%

Air pollution, oxidative stress and dietary supplementation: a review

Romieu

Castro-Giner²,

Künzli³

et al. 2008

European Respiratory Journal

220

157

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The aim of the present review was to provide an up-to-date overview of the biological and epidemiological evidence of the role of oxidative stress as a major underlying feature of the toxic effect of air pollutants, and the potential role of dietary supplementation in enhancing antioxidant defences.A bibliographic search was conducted through PubMed. The keywords used in the search were ''air pollutant'', ''oxidative stress'', ''inflammation'', ''antioxidant polyunsaturated fatty acids'' and ''genetics''. In addition, the authors also searched for biomarkers of oxidative stress and nutrients.The review presents the most recent data on: the biological and epidemiological evidence of the oxidative stress response to air pollutants; the role of dietary supplementation as a modulator of these effects; and factors of inter-individual variation in human response. The methodology for further epidemiological studies will be discussed in order to improve the current understanding on how nutritional factors may act.There is substantial evidence that air pollution exposure results in increased oxidative stress and that dietary supplementation may play a modulating role on the acute effect of air pollutants. Further epidemiological studies should address the impact of supplementation strategies in the prevention of air-pollution-related long-term effects in areas where people are destined to be exposed for the distant future.

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“…NF-κB is present in the cytosol in an inactive form linked to its inhibitory protein, and is being activated by stimuli like cytokines and oxidants (Li & Verma, 2002). Jimenez et al (2000) have shown in studies in vitro, using both macrophage cell lines and alveolar and bronchial epithelial cells, that oxidants cause the release of inflammatory mediators, such as IL-8, IL-1 and NO, and that these events are associated with increased expression of the genes for these inflammatory mediators and increased activation of NF-κB. NF-κB is highly expressed in CD4 + and CD8 + lymphocytes, macrophages, and monocytes in patients with COPD (Aldonyte et al, 2003).…”

Section: Bronchial Epithelial and Endothelial Cellsmentioning

confidence: 99%

The role of oxidative stress in lung injury induced by cigarette smoke

Kluchová

Tkáčová

2006

Biologia

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Oxidative stress is a damaging process resulting from an imbalance between excessive generation of oxidant compounds and insufficient antioxidant defence mechanisms. Oxidative stress plays a crucial role in the initiation and progression of cigarette smoke-induced lung injury, deterioration in lung functions, and development of chronic obstructive pulmonary disease (COPD). In smokers and in patients with COPD, the increased oxidant burden derives from cigarette smoke per se, and from activated inflammatory cells releasing enhanced amounts of reactive oxygen and nitrogen species (ROS, RNS, respectively). Although mild oxidative stress resulting from cigarette smoking leads to the upregulation of the antioxidative enzymes synthesis in the lungs, high levels of ROS and RNS observed in patients with COPD overwhelm the antioxidant enzymes capacities, resulting in oxidant-mediated lung injury and cell death. In addition, depletion of antioxidative systems in the systemic circulation was consistently observed in such patients. The imbalance between the generation of ROS/RNS and antioxidant capacities -the state of "oxidative stress" -is one of the major pathophysiologic hallmarks in the development of COPD. Detrimental effects of oxidative stress include impairment of membrane functions, inactivation of membrane-bound receptors and enzymes, and increased tissue permeability. In addition, oxidative stress aggravates the inflammatory processes in the lungs, and contributes to the worsening of the protease-antiprotease imbalance. Several markers of oxidative stress, such as increases in lipid peroxidation products and reductions in glutathione peroxidase activity, have been shown to be related to the reductions in pulmonary functions. In the present article we review the current knowledge about the vicious cycle of cigarette smoking, oxidative stress, and inflammation in the pathogenesis of COPD.

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Activation of NF-κB by PM10 Occurs via an Iron-Mediated Mechanism in the Absence of IκB Degradation

Cited by 173 publications

References 46 publications

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

Air pollution, oxidative stress and dietary supplementation: a review

The role of oxidative stress in lung injury induced by cigarette smoke

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