J. Clin. Invest.

1996

DOI: 10.1172/jci118598

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Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion.

Korbinian Brand¹,

Gerhard Rogler³

et al.

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Introduction2

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And Vcam-was Markedly Decreased In Blood Vessels Transfected1

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Cited by 744 publications

(489 citation statements)

References 45 publications

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“…Representative data of three experiments are shown. [2,63,64]. Under certain disease conditions it may be beneficial to modulate the expression of these molecules [65].…”

Section: Discussionmentioning

confidence: 99%

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

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²

,

³

et al. 1998

Journal of Leukocyte Biology

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Abstract:We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-B (NF-B). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of I B-␣ and -␤, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-B binding activity and NF-B transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1␤ (IL-1␤), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of I B-␣ and -␤, efficiently blocked the production of TNF and, to a lesser extent, IL-1␤, whereas that of IL-8 was not inhibited. The expression of NF-B-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.

“…Representative data of three experiments are shown. [2,63,64]. Under certain disease conditions it may be beneficial to modulate the expression of these molecules [65].…”

Section: Discussionmentioning

confidence: 99%

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

¹

,

²

,

³

et al. 1998

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Abstract:We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-B (NF-B). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of I B-␣ and -␤, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-B binding activity and NF-B transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1␤ (IL-1␤), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of I B-␣ and -␤, efficiently blocked the production of TNF and, to a lesser extent, IL-1␤, whereas that of IL-8 was not inhibited. The expression of NF-B-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.

“…9,10 In situ detection of nuclear p65 and p50 has revealed NF B activity within human atheroma, eg in intimal VSMC but not in undiseased arteries. 11,12 Moreover, NF B was induced in VSMC after arterial balloon injury. 13,14 NF B activity appears to be essential for the proliferation of VSMC, which was demonstrated by the selective inhibition of VSMC growth after transfer of the NF B inhibitor protein I Bα in cultured VSMC.…”

Section: And Vcam-was Markedly Decreased In Blood Vessels Transfectedmentioning

confidence: 99%

Inhibition of intimal hyperplasia after balloon injury in rat carotid artery model using cis-element ‘decoy’ of nuclear factor-kB binding site as a novel molecular strategy

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³

et al. 2001

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The transcription factor, NFkB, plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes involved in atherosclerosis and lesion formation after vascular injury. We hypothesized that synthetic doublestranded DNA with high affinity for NFkB may be introduced as a 'decoy' cis element to bind the transcription factor, and block gene activation, resulting in an effective therapeutic agent for treating intimal hyperplasia. In vivo transfection of NFkB decoy oligodeoxynucleotides (ODN) into ballooninjured rat carotid artery resulted in the inhibition of neointimal formation at 14 days after injury as compared with vessels transfected with scrambled ODN (P Ͻ 0.01). It is of importance to note that in the vessels

“…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. 22,23 Whether or not Rap1 exerts pro-atherogenic effects is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…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. 22,23 Whether or not Rap1 exerts pro-atherogenic effects is unknown. Thus, the present study was designed to test the hypothesis that Rap1 modulates inflammatory processes via the NFkB signaling cascade in macrophages, endothelial and smooth muscle cells.…”

Section: Introductionmentioning

confidence: 99%

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

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³

et al. 2015

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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.

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