Role of nuclear factor‐kappa B in atherogenesis

Brand, Korbinian; Page, Sharon; Walli, Autar K.; Neumeier, D.; Baeuerle, P.A.

doi:10.1113/expphysiol.1997.sp004025

Cited by 161 publications
(94 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it must be noted that others have also shown that vitamin C can also suppress HIV expression in an NF-B-independent manner (43). Other NF-B-dependent pathologies in which beneficial effects for vitamin C have been claimed include cardiovascular disease (7,16) and cancer (6, 10 -13).…”

Section: Discussionmentioning
confidence: 99%

“…The inducible, higher eukaryotic transcription factor NF-B regulates the expression of a number of cellular genes involved in immune and inflammatory responses (10), has antiapoptotic effects (11)(12)(13), is involved in the replication of several viruses (10), most notably HIV-1 (14), and has been implicated in the initiation and development of atherosclerosis (15,16). It is activated by diverse pathogenic signals, including the proinflammatory cytokines IL-1 and TNF (10).…”

mentioning
confidence: 99%

See 1 more Smart Citation
Vitamin C Inhibits NF-κB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase
Bowie
¹
,
O’Neill
²

2000
The Journal of Immunology
298
9
173
2
View full text Add to dashboard Cite
The transcription factor NF-κB is a central mediator of altered gene expression during inflammation, and is implicated in a number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the activation of NF-κB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-κB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-κB. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-κB were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-κBα (inhibitory protein that dissociates from NF-κB), due to inhibition of I-κB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase, because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580 reversed the inhibitory effect of vitamin C on IKK activity, I-κBα phosphorylation, and NF-κB activation. The results identify p38 as an intracellular target for high dose vitamin C.
show abstract

Section: Discussionmentioning
confidence: 99%

mentioning
confidence: 99%

Vitamin C Inhibits NF-κB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase
Bowie
¹
,
O’Neill
²

2000
The Journal of Immunology
298
9
173
2
View full text Add to dashboard Cite

The transcription factor NF-κB is a central mediator of altered gene expression during inflammation, and is implicated in a number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the activation of NF-κB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-κB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-κB. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-κB were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-κBα (inhibitory protein that dissociates from NF-κB), due to inhibition of I-κB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase, because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580 reversed the inhibitory effect of vitamin C on IKK activity, I-κBα phosphorylation, and NF-κB activation. The results identify p38 as an intracellular target for high dose vitamin C.

show abstract

“…[18][19][20] Being a major transcription factor regulating inflammatory responses, NFkB has been linked to the pathogenesis of atherosclerosis. 12,21 Macrophages, endothelial cells and smooth muscle cells within atherosclerotic lesions exhibit enhanced NFkB activity. 22 These cells cooperatively contribute to the pro-inflammatory environment within the atherosclerotic lesions by enhancing the expression of adhesion molecule and the release of chemokines and cytokines.…”

Section: Introductionmentioning
confidence: 99%

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions
Cai
¹
,
Sukhova
²
,
Wong
³

et al. 2015
Cell Cycle
74
2
56
0
View full text Add to dashboard Cite

Repressor activator protein 1 (Rap1) is essential for maintaining telomere length and structural integrity, but it also exerts other non-telomeric functions. The present study tested the hypothesis that Rap1 is released into the cytoplasm and induces production of pro-inflammatory cytokines via nuclear factor kappa B (NFkB) signaling in macrophages, a cell type involved in the development and progression of atherosclerotic lesions. Western blotting analysis confirmed that Rap1 was present in the cytoplasm of differentiated human monocytic leukemia cells (THP-1, a macrophage-like cell line). Co-immunoprecipitation assay revealed a direct interaction between Rap1 and I kappa B kinase (IKK). Knockdown of Rap1 suppressed lipopolysaccharide-mediated activation of NFkB, and phosphorylation of inhibitor of kappa B a (IkBa) and p65 in THP-1 macrophages. The reduction of NFkB activity was paralleled by a decreased production of NFkB-dependent pro-inflammatory cytokines and an increased expression of IkBa (native NFkB inhibitor) in various macrophage models with pro-inflammatory phenotype, including THP-1, mouse peritoneal macrophages and bone marrow-derived M1 macrophages. These changes were observed selectively in pro-inflammatory macrophages but not in bone marrow-derived M2 macrophages (with an anti-inflammatory phenotype), mouse lung endothelial cells, human umbilical vein endothelial cells or human aortic smooth muscle cells. Immunostaining revealed that Rap1 was localized mainly in macrophage-rich areas in human atherosclerotic plaques and that the presence of Rap1 was positively correlated with the advancement of the disease process. In pro-inflammatory macrophages, Rap1 promotes cytokine production via NFkB activation favoring a pro-inflammatory environment which may contribute to the development and progression of atherosclerosis.

show abstract

“…4 -6 Nuclear factor (NF)-B, which can be activated by several of these stimuli, including cytokines and oxidized lipids, 7,8 has shown to be an important transcription factor responsible for modulating this enhanced proinflammatory status. 9 In addition, hemodynamic forces have been shown to modulate endothelial inflammation and the development of atherosclerotic plaques. 10,11 Throughout the past decade, inbred mouse models of accelerated atherosclerosis have also significantly contributed to the large body of pathophysiological knowledge on the development of atherosclerosis.…”

mentioning
confidence: 99%

Distinctive Expression of Chemokines and Transforming Growth Factor-β Signaling in Human Arterial Endothelium during Atherosclerosis
Volger
¹
,
Fledderus
²
,
Kisters
³

et al. 2007
The American Journal of Pathology
62
4
55
1
View full text Add to dashboard Cite

Knowledge about the in vivo role of endothelium in chronic human atherosclerosis has mostly been derived by insights from mouse models. Therefore, we set out to establish by microarray analyses the gene expression profiles of endothelium from human large arteries, as isolated by laser microbeam microdissection, having focal atherosclerosis of the early or the advanced stage. Within individual arteries, the endothelial transcriptomes of the lesional and unaffected sides were compared pairwise, thus limiting genetic and environmental confounders. Specific endothelial signature gene sets were identified with changed expression levels in either early (n ‫؍‬ 718) or advanced atherosclerosis (n ‫؍‬ 403), relative to their paired plaque-free controls. Gene set enrichment analysis identified distinct sets of chemokines and differential enrichments of nuclear factor-B-, p53-, and transforming growth factor-␤-related genes in advanced plaques.

show abstract

Role of nuclear factor‐kappa B in atherogenesis

Cited by 161 publications

References 16 publications

Vitamin C Inhibits NF-κB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase

Vitamin C Inhibits NF-κB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions

Distinctive Expression of Chemokines and Transforming Growth Factor-β Signaling in Human Arterial Endothelium during Atherosclerosis

Contact Info

Product

Resources

About