Hypoxia transcriptionally induces macrophage-inflammatory protein-3α/CCL-20 in primary human mononuclear phagocytes through nuclear factor (NF)-κB

Battaglia, Florinda; Delfino, Silvana; Merello, Elisa; Puppo, Maura; Piva, Roberto; Varesio, Luigi; Bosco, Maria Carla

doi:10.1189/jlb.0607349

Cited by 48 publications

(32 citation statements)

References 62 publications

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“…It is noteworthy that NF-B has also been involved in the modulation of CCL20 by other mediators such as TNF␣ in a human cancer cell line, 38 prolactin in keratinocytes, 35 or hypoxia in primary human monocytes/ macrophages. 39 Taken together these results emphasize the role of NF-B in the modulation of CCL20 by lipoproteins and other inducers. Concerning the mechanism involved in such effect, lipoprotein receptors do not seem to play a major role.…”

Section: Discussionmentioning

confidence: 62%

CCL20 Is Increased in Hypercholesterolemic Subjects and Is Upregulated By LDL in Vascular Smooth Muscle Cells

Calvayrac

Rodríguez-Calvo

Alonso

et al. 2011

ATVB

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Objective-Our aim was to analyze the regulation of CC Chemokine ligand 20 (CCL20) by LDL in human vascular smooth muscle cells (VSMC). Methods and Results-In asymptomatic subjects, circulating CCL20 levels were higher in patients with hypercholesterolemia (18.5Ϯ3.2 versus 9.1Ϯ1.3 pg/mL; PϽ0.01). LDL induced the expression of CCL20 in VSMC in a dose-and time-dependent manner. Increased levels of CCL20 secreted by LDL-treated VSMC significantly induced human lymphocyte migration, an effect reduced by CCL20 silencing. The upregulation of CCL20 by LDL was dependent on the activation of kinase signaling pathways and NF-B. By site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we identified a NF-B site (Ϫ80/Ϫ71) in CCL20 promoter critical for LDL responsiveness. Lysophosphatidic acid mimicked the upregulation of CCL20 induced by LDL, and minimal oxidation of LDL increased the ability of LDL to induce CCL20 through a mechanism that involves lysophosphatidic acid receptors. CCL20 was overexpressed in atherosclerotic lesions from coronary artery patients, colocalizing with VSMC. CCL20 was detected in conditioned media from healthy human aorta and its levels were significantly higher in secretomes from carotid endarterectomy specimens. A therosclerosis is essentially an inflammatory chronic disease. [1][2][3] Inflammation is a necessary response to injury and infection. Virtually all cardiovascular risk factors are capable of promoting an inflammatory response; among them, however, elevated levels of plasma cholesterol, in particular LDL, are recognized as one of the most important risk factors for atherosclerosis. 4,5 The inflammatory response involves the coordinated regulation of cell adhesion and migration and the establishment of a chemotactic gradient that guides inflammatory cells to damaged tissues. Key elements in this communication network are cytokines and chemokines, which orchestrate the recruitment, survival, expansion, and effector function of inflammatory cells. 6 -8 Chemokines are a superfamily of structurally related small chemotactic cytokines that control leukocyte function through interactions with their cognate 7-transmembranedomain G protein-coupled receptors. Monocytes/macrophages and T lymphocytes are the most abundant inflammatory cells found in atherosclerotic plaques, 9,10 but also B cells, dendritic cells, and neutrophils contribute to the pathogenesis of atherosclerosis. 9,11,12 Native and modified LDL modulate the expression of key genes involved in the recruitment and trafficking of inflammatory cells including cellular adhesion molecules and chemokines such as monocyte chemotactic protein 1. 4,5,[13][14][15] Recent studies have implicated other chemokines in atherosclerosis and have extended the knowledge about the regulation of chemokines/chemokine receptors on vascular cells, 6 -8 but the complete picture of these molecules involved in atherogenesis is not completely understood. Conclusion-ThisIncreasing data involving innate and adapti...

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Section: Discussionmentioning

confidence: 62%

CCL20 Is Increased in Hypercholesterolemic Subjects and Is Upregulated By LDL in Vascular Smooth Muscle Cells

Calvayrac

Rodríguez-Calvo

Alonso

et al. 2011

ATVB

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“…Increased p50 levels do not appear to mediate Notch induction of NF-kB activity in Raw cells (Fig. 5D), but we cannot rule out that this could arrive in particular promoter contexts, as the role of p50 depends largely on that [29,31]. NF-kB p65 levels seem to be less affected by Notch1 signaling.…”

Section: Discussionmentioning

confidence: 94%

“…Although p50 homodimers have been classically considered as transcriptional inhibitory proteins, recent works have shown that in some promoter contexts they are able to increase NF-kBdependent transcription [29,31]. To evaluate whether Notch1 could modify p50 transcriptional activity, we transfected increasing amounts of a p50 expression vector and an NF-kBluciferase reporter construct in Raw-NIC or Raw control cells.…”

Section: Mechanism Of Notch-nf-jb Crosstalkmentioning

confidence: 99%

“…However, we could not detect an increase of p65 expression in Raw-NIC cells, suggesting that this is not a factor helping to explain its favored translocation to the nucleus. Nevertheless, increased p65 levels were detected in Raw-Dll4 cells, suggesting that activation of other Notch family members, besides Notch1, may also affect NF-kB activity.Although p50 homodimers have been classically considered as transcriptional inhibitory proteins, recent works have shown that in some promoter contexts they are able to increase NF-kBdependent transcription [29,31]. To evaluate whether Notch1 could modify p50 transcriptional activity, we transfected increasing amounts of a p50 expression vector and an NF-kBluciferase reporter construct in Raw-NIC or Raw control cells.…”

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confidence: 99%

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Notch1 upregulates LPS‐induced macrophage activation by increasing NF‐κB activity

Monsalve¹,

Ruiz-García²,

Baladrón³

et al. 2009

Eur J Immunol

138

172

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Macrophages present different Notch receptors and ligands on their surface. Following macrophage activation by LPS or other TLR ligands, Notch1 expression is upregulated. We report here that Notch signaling increases both basal and LPS-induced NF-jB activation, favoring the expression of genes implicated in the inflammatory response, such as the cytokines TNF-a and IL-6, or enzymes, such as iNOS. Delta4 seems to be the most effective ligand to induce Notch activation and increasing NF-jB transcriptional activity in macrophages. We show that Notch1 signaling promotes NF-jB translocation to the nucleus and DNA binding by increasing both phosphorylation of the IjB kinase a/b complex and the expression of some NF-jB family members. Treatment of macrophages with the c-secretase inhibitor DAPT, which prevents the cleavage and activation of Notch receptors, inhibits all these processes, diminishing NF-jB activity following LPS stimulation. Additionally, we show that the active intracellular Notch fragment can directly interact with TNF-a and iNOS promoters. Our results suggest that Notch signaling results in an amplification of the macrophage-dependent inflammatory response by enhancing NF-jB signaling.Key words: Macrophages . NF-kB . Notch IntroductionMacrophages are essential cells for the innate immune response. They discriminate between pathogens and self through signals triggered by TLR, which recognize different pathogens' components, such as LPS, lipoproteins, or dsRNA, among others [1]. Activation of most TLR on the macrophage surface triggers a complex signaling pathway, which involves NF-kB activation (reviewed in [2]). In the classical NF-kB pathway, a ternary IkB kinase (IKK) complex, formed by IKK-a, IKK-b, and NF-kB essential modulator, is responsible for inducing IkB phosphorylation, allowing the release of sequestered cytoplasmic NF-kB from IkB and its translocation to the nucleus. Once in the nucleus, NF-kB controls the expression of multiple genes implicated in the inflammatory response, including cytokines, effector enzymes such as iNOS and COX-2, and adhesion molecules [2].Notch proteins encompass a family of transmembrane receptors composed of an extracellular subunit linked to a transmembrane and intracellular subunit via heterodimerization domains [3]. Ligand binding induces proteolytic cleavage of the transmembrane and intracellular receptor subunit by several proteases, including g-secretase [4], allowing the release of the intracellular domain of Notch (NIC), which then translocates to the nucleus and converts the CBF1 factor from a repressor to a transcriptional activator. Some NIC target genes have been characterized, including basic-helix-loop-helix transcription factors belonging to 2556the hairy/enhancer of split (HES) gene family [3]. Although some CBF1-independent Notch signaling can occur, its mechanism of action is not well characterized yet [5].Notch signaling is an evolutionarily conserved pathway that controls different aspects of tissue development and homeostasis [6]. In cells o...

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“…38 Although dendritic cells accumulate HIF-1␣ in hypoxia, 39 immature forms of this cell type up-regulate other hypoxiaresponsive genes, such as CCL20 via up-regulated p50/p50 NF-B homodimers rather than HIFs. 40 A study of the responses of such related myeloid cell types to identical hypoxic conditions would be interesting but beyond the remit of this study.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

Fang

Hughes

Murdoch

et al. 2009

Blood

293

268

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Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours.

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Hypoxia transcriptionally induces macrophage-inflammatory protein-3α/CCL-20 in primary human mononuclear phagocytes through nuclear factor (NF)-κB

Cited by 48 publications

References 62 publications

CCL20 Is Increased in Hypercholesterolemic Subjects and Is Upregulated By LDL in Vascular Smooth Muscle Cells

CCL20 Is Increased in Hypercholesterolemic Subjects and Is Upregulated By LDL in Vascular Smooth Muscle Cells

Notch1 upregulates LPS‐induced macrophage activation by increasing NF‐κB activity

Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

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