Inhibitor of NF-κB Kinases α and β Are Both Essential for High Mobility Group Box 1-Mediated Chemotaxis

Penzo, Marianna; Molteni, Raffaella; Suda, Tomomi; Samaniego, Sylvia; Raucci, Angela; Habiel, David M.; Miller, Frederick W.; Jiang, Hui Ping; Li, Jun; Pardi, Ruggero; Palumbo, Roberta; Olivotto, Eleonora; Kew, Richard R.; Bianchi, Marco E.; Marcu, Kenneth B.

doi:10.4049/jimmunol.0903131

Cited by 87 publications

(110 citation statements)

References 81 publications

(125 reference statements)

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“…17 Phosphorylation of IKK is essential for inflammation triggering macrophage chemotaxis. 19 As already shown in other cell types, 21,22 SGK1 effectively regulates transcription by upregulating NF-κB activity through phosphorylation and activation of IKKα/β. Thus, SGK1 enhances the ability of IKKα/β to phosphorylate endogenous IκBα.…”

Section: Discussionmentioning

confidence: 85%

“…9,18 The proinflammatory transcription factor NF-κB is retained inactive in the cytoplasm through association with the inhibitor κB (IκB) protein. 19 On phosphorylation, IκB kinase (IKK) phosphorylates IκB thus initiating the ubiquitination and subsequent degradation of IκB followed by translocation of NF-κB into the nucleus with initiation of NF-κB-dependent gene expression. 2,20 Atherogenesis requires multiple cell signaling mechanisms involving different protein kinases such as phosphoinositide-3 kinase (PI3K).…”

mentioning

confidence: 99%

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Pivotal Role of Serum- and Glucocorticoid-Inducible Kinase 1 in Vascular Inflammation and Atherogenesis

Borst

Schaub

Walker

et al. 2015

ATVB

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Objective— Atherosclerosis, an inflammatory disease of arterial vessel walls, requires migration and matrix metalloproteinase (MMP)-9–dependent invasion of monocytes/macrophages into the vascular wall. MMP-9 expression is stimulated by transcription factor nuclear factor-κB, which is regulated by inhibitor κB (IκB) and thus IκB kinase. Regulators of nuclear factor-κB include serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored involvement of SGK1 in vascular inflammation and atherogenesis. Approach and Results— Gene-targeted apolipoprotein E (ApoE)–deficient mice without ( apoe −/− sgk1 +/+ ) or with ( apoe −/− sgk1 −/− ) additional SGK1 knockout received 16-week cholesterol-rich diet. According to immunohistochemistry atherosclerotic lesions in aorta and carotid artery, vascular CD45 + leukocyte infiltration, Mac-3 + macrophage infiltration, vascular smooth muscle cell content, MMP-2, and MMP-9 positive areas in atherosclerotic tissue were significantly less in apoe −/− sgk1 −/− mice than in apoe −/− sgk1 +/+ mice. As determined by Boyden chamber, thioglycollate-induced peritonitis and air pouch model, migration of SGK1-deficient CD11b + F4/80 + macrophages was significantly diminished in vitro and in vivo. Zymographic MMP-2 and MMP-9 production, MMP-9 activity and invasion through matrigel in vitro were significantly less in sgk1 −/− than in sgk1 +/+ macrophages and in control plasmid–transfected or inactive K127N SGK1-transfected than in constitutively active S422D SGK1-transfected THP-1 cells. Confocal microscopy revealed reduced macrophage number and macrophage MMP-9 content in plaques of apoe −/− sgk1 −/− mice. In THP-1 cells, MMP-inhibitor GM6001 (25 μmol/L) abrogated S422D SGK1-induced MMP-9 production and invasion. According to reverse transcription polymerase chain reaction, MMP-9 transcript levels were significantly reduced in sgk1 −/− macrophages and strongly upregulated in S422D SGK1-transfected THP-1 cells compared with control plasmid–transfected or K127N SGK1-transfected THP-1 cells. According to immunoblotting and confocal microscopy, phosphorylation of IκB kinase and inhibitor κB and nuclear translocation of p50 were significantly lower in sgk1 −/− macrophages than in sgk1 +/+ macrophages and significantly higher in S422D SGK1-transfected THP-1 cells than in control plasmid–transfected or K127N SGK1-transfected THP-1 cells. Treatment of S422D SGK1-transfected THP-1 cells with IκB kinase-inhibitor BMS-345541 (10 μmol/L) abolished S422D SGK1-induced increase of MMP-9 transcription and gelatinase activity. Conclusions— SGK1 plays a pivotal role in vascular inflammation during atherogenesis. SGK1 participates in the regulation of monocyte/macrophage migration and MMP-9 transcription via regulation of nuclear factor-κB.

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

Pivotal Role of Serum- and Glucocorticoid-Inducible Kinase 1 in Vascular Inflammation and Atherogenesis

Borst

Schaub

Walker

et al. 2015

ATVB

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“…Nilvadipine has been shown to inhibit nuclear factor-κB (NFκB)-dependent transcription (38) and, as expected for an NFκB inhibitor, nilvadipine users have reduced plasma cytokine levels (39). Interestingly, both RAGE and BACE-1 expression are regulated by NFκB (40)(41)(42)(43). In particular, inhibition of NFκB signaling decreases RAGE expression in endothelial cells (44) and reduces Aβ production and BACE-1 expression levels (21,45,46).…”

Section: Discussionmentioning

confidence: 90%

Selective Antihypertensive Dihydropyridines Lower Aβ Accumulation by Targeting both the Production and the Clearance of Aβ across the Blood-Brain Barrier

Paris

Bachmeier

Patel

et al. 2010

Mol Med

102

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“…The inhibition of NF-kB activation with an adenovirus-expressing IkBa mutation can attenuate HMGB1 translocation in cultured cells, as well as in a cecal ligation and puncture-induced animal model of sepsis (66). In addition, inhibitors of IKKa and IKKb have been shown to inhibit HMGB1-induced chemotaxis (67). In this study, the association between the increased levels of extracellular HMGB1 and hyperoxiainduced NF-kB activation suggests that NF-kB plays a role in oxidative stressinduced HMGB1 release.…”

Section: Ea Inhibits Hmgb1 Release From Hyperoxia-exposed Macrophagesmentioning

confidence: 99%

The Compromise of Macrophage Functions by Hyperoxia Is Attenuated by Ethacrynic Acid via Inhibition of NF-κB–Mediated Release of High-Mobility Group Box-1

Wang

Gorasiya

Antoine

et al. 2015

Am J Respir Cell Mol Biol

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The prolonged exposure to hyperoxia can compromise macrophage functions and contribute to the development of ventilator-associated pneumonia. High levels of extracellular high-mobility group box-1 (HMGB1) in the airways of mice exposed to hyperoxia can directly cause macrophage dysfunction. Hence, inhibition of the release of nuclear HMGB1 into the extracellular milieu may help to maintain macrophage functions under hyperoxic conditions. The present study investigates whether ethacrynic acid (EA) affects hyperoxiainduced HMGB1 release from macrophages and improves their functions. Macrophage-like RAW 264.7 cells and bone marrowderived macrophages were exposed to different concentrations of EA for 24 hours in the presence of 95% O 2 . EA significantly decreased the accumulation of extracellular HMGB1 in cultured media. Importantly, the phagocytic activity and migration capability of macrophages were significantly enhanced in EA-treated cells. Interestingly, hyperoxia-induced NF-kB activation was also inhibited in these cells. To determine whether NF-kB plays a role in hyperoxia-induced HMGB1 release, BAY 11-7082, an inhibitor of NF-kB activation, was used. Similar to EA, BAY 11-7082 significantly inhibited the accumulation of extracellular HMGB1 and improved hyperoxia-compromised macrophage migration and phagocytic activity. Furthermore, 24-hour hyperoxic exposure of macrophages caused hyperacetylation of HMGB1 and its subsequent cytoplasmic translocation and release, which were inhibited by EA and BAY 11-7082. Together, these results suggest that EA enhances hyperoxia-compromised macrophage functions by inhibiting HMGB1 hyperacetylation and its release from macrophages, possibly through attenuation of the NF-kB activation. Therefore, the activation of NF-kB could be one of the underlying mechanisms that mediate hyperoxia-compromised macrophage functions.Keywords: hyperoxia; macrophage; high-mobility group box-1; phagocytosis; NF-kB Clinical RelevanceWe demonstrate that modulating extracellular levels of highmobility group box-1 by inhibitors to NF-kB activation could be used as a potential approach to improve hyperoxiacompromised macrophage functions. If these results can be translated to humans, it is possible that ethacrynic acid could be used as part of the treatment for patients with ventilatorassociated pneumonia.

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Inhibitor of NF-κB Kinases α and β Are Both Essential for High Mobility Group Box 1-Mediated Chemotaxis

Abstract: Material

Cited by 87 publications

References 81 publications

Pivotal Role of Serum- and Glucocorticoid-Inducible Kinase 1 in Vascular Inflammation and Atherogenesis

Pivotal Role of Serum- and Glucocorticoid-Inducible Kinase 1 in Vascular Inflammation and Atherogenesis

Selective Antihypertensive Dihydropyridines Lower Aβ Accumulation by Targeting both the Production and the Clearance of Aβ across the Blood-Brain Barrier

The Compromise of Macrophage Functions by Hyperoxia Is Attenuated by Ethacrynic Acid via Inhibition of NF-κB–Mediated Release of High-Mobility Group Box-1

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