Tumour necrosis factor‐α stimulates expression of TNF‐α converting enzyme in endothelial cells

Bzowska, Monika; Jura, Natalia; Lassak, Adam; Black, Roy A.; Bereta, Joanna

doi:10.1111/j.1432-1033.2004.04215.x

Cited by 58 publications

(57 citation statements)

References 47 publications

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“…Among these, TNF␣ was shown to increase TACE mRNA levels in endothelial cells, suggesting a role for this cytokine in the regulation of TACE in other cell types (12). It is well known that large amounts of TNF␣ are present in the synovial membrane of arthritic joints, a diseased tissue also characterized by the presence of numerous hypoxic areas (37,38).…”

Section: Resultsmentioning

confidence: 99%

“…Surprisingly, few agents, which are known to enhance ectodomain shedding of proteins have been documented for their role in the regulation of TACE expression. Increased levels of TACE mRNA were observed in murine retinal endothelial cells or human endothelial cells exposed to vascular endothelial growth factor (11) or TNF␣ (12), respectively. In addition, several studies have shown that TACE expression is elevated under pathological conditions.…”

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confidence: 96%

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Hypoxia-inducible Factor Mediates Hypoxic and Tumor Necrosis Factor α-induced Increases in Tumor Necrosis Factor-α Converting Enzyme/ADAM17 Expression by Synovial Cells

Charbonneau¹,

Harper²,

Grondin³

et al. 2007

Journal of Biological Chemistry

104

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Chronic hypoxia and inflammatory cytokines are hallmarks of inflammatory joint diseases like rheumatoid arthritis (RA), suggesting a link between this microenvironment and central pathological events. Because TACE/ADAM17 is the predominant protease catalyzing the release of tumor necrosis factor ␣ (TNF␣), a cytokine that triggers a cascade of events leading to RA, we examined the regulation of this metalloprotease in response to hypoxia and TNF␣ itself. We report that low oxygen concentrations and TNF␣ enhance TACE mRNA levels in synovial cells through direct binding of hypoxia-inducible factor-1 (HIF-1) to the 5 promoter region. This is associated with elevated TACE activity as shown by the increase in TNF␣ shedding rate. By the use of HIF-1-deficient cells and by obliterating NF-B activation, it was determined that the hypoxic TACE response is mediated by HIF-1 signaling, whereas the regulation by TNF␣ also requires NF-B activation. As a support for the in vivo relevance of the HIF-1 axis for TACE regulation, immunohistological analysis of TACE and HIF-1 expression in RA synovium indicates that TACE is up-regulated in both fibroblast-and macrophage-like synovial cells where it localizes with elevated expression of both HIF-1 and TNF␣. These findings suggest a mechanism by which TACE is increased in RA-affected joints. They also provide novel mechanistic clues on the influence of the hypoxic and inflammatory microenvironment on joint diseases.Tumor necrosis factor-␣ converting enzyme (TACE) 2 or ADAM17 was initially described as the predominant enzyme responsible for the physiological cleavage of membrane-anchored tumor necrosis factor-␣ (TNF␣), releasing it in soluble form (1, 2). This enzyme belongs to the ADAM (a disintegrin and metalloprotease domain) family of transmembrane, multidomain zinc metalloproteinases (3) and is expressed in a wide variety of cell types, including TNF␣ non-producing cells (1). Beside TNF␣, TACE was also shown to solubilize a wide variety of proteins including the receptors TNFR-I and TNFR-II (4), interleukin-1RII (5), interleukin-6R (6), and macrophage/colony-stimulating factor-R (7), the cytokine transforming growth factor-␣ (4), members of the membrane-bound epidermal growth factor family (4), the Notch receptor (8), the chemokine fractalkine (9), L-selectin (4), and the ␤-amyloid precursor protein (10). The importance of TACE substrates in a variety of physiological functions, including development, is underscored by the fact that in vivo inhibition of TACE or disruption of the TACE gene results in the death of mice between embryonic day 17.5 and the first day after birth, due to a number of developmental defects. In addition, the implication of TACE substrates in immunoregulation has made this enzyme an efficient therapeutic target in the treatment of a number of pathological conditions including airway inflammation, cancer, and arthritis.Because of the pathophysiological importance of TACE-mediated shedding, several studies have addressed the mechanism of TACE regulation. Sur...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 96%

Hypoxia-inducible Factor Mediates Hypoxic and Tumor Necrosis Factor α-induced Increases in Tumor Necrosis Factor-α Converting Enzyme/ADAM17 Expression by Synovial Cells

Charbonneau¹,

Harper²,

Grondin³

et al. 2007

Journal of Biological Chemistry

104

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“…Few studies have addressed this issue in vitro showing that certain agonists transcriptionally up-regulate the levels of this metalloprotease, whereas others can down-regulate the metalloprotease post-transcriptionally (13)(14)(15)(16). On the other hand, several authors have analyzed the levels of ADAM17 mRNA in tumor samples, and others have analyzed its protein levels, and both types of studies have concluded that ADAM17 is frequently overexpressed in human tumors (18 -20, 22-24, 37).…”

Section: Discussionmentioning

confidence: 99%

“…Certain cytokines and growth factors up-regulate the transcription of ADAM17 in endothelial and human monocyte-like cells (13,14). On the other hand, the expression of ADAM17 can be post-transcriptionally down-modulated by phorbol esters and interferons (15,16).…”

mentioning

confidence: 99%

Post-transcriptional Up-regulation of ADAM17 upon Epidermal Growth Factor Receptor Activation and in Breast Tumors

Santiago-Josefat

Esselens

Bech-Serra

et al. 2007

Journal of Biological Chemistry

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ADAM17 is a transmembrane metalloprotease involved in the proteolytic release of the extracellular domain of many cell surface molecules, a process known as ectodomain shedding. Despite its likely participation in tumor progression and its current consideration as a therapeutic target, very little is known about the regulation of the expression of ADAM17. Here we show that long term treatment with epidermal growth factor (EGF) leads to a marked increase in the levels of ADAM17. EGF receptor activation does not affect the levels of the mRNA that encodes for, or the rate of synthesis of, ADAM17 but increases its half-life. The effect of EGF is biologically relevant because it increases the shedding of several substrates of ADAM17, including the desmosomal cadherin Dsg-2. Analysis of protein and mRNA levels in mammary tumor samples shows that in vivo the levels of ADAM17 can also be controlled post-transcriptionally. Finally, we show that both the shed extracellular domains of Dsg-2 and ADAM17 are frequently expressed in tumors, further supporting the participation of the metalloprotease in malignant progression.The ADAMs 2 constitute a large family of transmembrane proteases involved in different physiological processes, including fertilization, heart development, angiogenesis, and neurogenesis (1, 2). Structurally, ADAMs are modular proteins containing the following recognizable domains: signal peptide, prodomain, cysteine-rich, epidermal growth factor (EGF)-like, transmembrane, and cytoplasmic (3). The prodomain, which keeps the enzyme in an inactive state, is typically removed during transit through the secretory pathway; thus, the metalloprotease reaches the plasma membrane in an active state. At the cell surface, certain ADAMs participate in the proteolytic removal of the ectodomain of a significant number of membrane-anchored proteins. This specialized type of proteolysis is known as ectodomain shedding and affects different cell surface molecules, including growth factors, growth factor receptors, and cell adhesion molecules (4).Increasing evidence points to a role of certain ADAMs, particularly the 17th member of the family, in the development of certain tumors (5). ADAM17, also know as tumor necrosis factor-␣-converting enzyme, participates in the activation of the epidermal growth factor receptor (EGFR) and related receptors (6), which play a crucial role in the development of different tumors of epidermal origin (7). All the ligands for the EGFR are synthesized as transmembrane molecules (8), and the inhibition of the shedding of their extracellular domains, carried out by ADAM17 and other ADAMs, prevents the activation of the EGFR in different experimental settings (see for example Refs. 9 -11). Therefore, metalloprotease inhibitors targeting ADAM17 have been proposed as anti-tumor drugs (reviewed in Ref. 12).Despite its importance, the regulation of the expression of ADAM17 remains poorly characterized. Certain cytokines and growth factors up-regulate the transcription of ADAM17 in endothelial and hum...

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“…ACE is induced by vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells (HUVEC) (Okabe et al, 1987;Saijonmaa et al, 2001b) or downregulated by TNF-a and interleukin (IL)1b in HUVECs (Saijonmaa et al, 2001a). TNF-a stimulates TACE expression in murine and human endothelial cell lines (Bzowska et al, 2004). Therefore, increased knowledge of the physiological mechanisms by which ACE and TACE are regulated is of particular interest in view of the comprehension of their roles in diseased conditions.…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of tumor necrosis factor-α-converting enzyme and angiotensin-converting enzyme by type I and II interferons in human normal and leukemic myeloid cells

et al. 2006

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The transmembrane metalloproteases angiotensin-converting enzyme (ACE) and tumor necrosis factor-a (TNF-a)-converting enzyme (TACE/ADAM-17) have been associated with inflammation, cancer progression and angiogenesis. Few investigations into the regulation of these enzymes by physiological stimuli have been reported. In this study, we investigated the influence of interferons (IFNs) type I (a, b) and II (c) on ACE and TACE expression of human leukemic NB4 cells and monocytes.We assessed the expression of proteases by reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence analyses. IFNc, but not type I IFNs, upregulated membrane ACE in a dose-and time-dependency and this was reflected by the increase of ACE enzymatic activity and ACE mRNA. ACE upregulation was dependent on protein synthesis. Treatment of the interferon responsive factor 1 (IRF1)-unresponsive HepG2 cell line with IFNc did not affect ACE expression, thus suggesting the participation of the IRF1 signaling pathway in IFNc-mediated ACE upregulation in myeloid cells. In contrast, both types of IFNs, in a dose-and time-dependent manner, downregulated surface TACE without affecting TACE transcript. Soluble TACE was not detected in the medium of IFN-treated cells. IFNc-mediated decrease of surface TACE in NB4 cells was reversible, and correlated with an increase in intracellular TACE, suggesting that cell surface TACE was internalized in response to IFNs. These findings, showing the presence of IFN-dependent controlled mechanisms by which ACE and TACE levels are regulated in human normal and leukemic myeloid cells, may have implications in the context of current investigations on the therapeutic potential of IFNs.

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Tumour necrosis factor‐α stimulates expression of TNF‐α converting enzyme in endothelial cells

Cited by 58 publications

References 47 publications

Hypoxia-inducible Factor Mediates Hypoxic and Tumor Necrosis Factor α-induced Increases in Tumor Necrosis Factor-α Converting Enzyme/ADAM17 Expression by Synovial Cells

Hypoxia-inducible Factor Mediates Hypoxic and Tumor Necrosis Factor α-induced Increases in Tumor Necrosis Factor-α Converting Enzyme/ADAM17 Expression by Synovial Cells

Post-transcriptional Up-regulation of ADAM17 upon Epidermal Growth Factor Receptor Activation and in Breast Tumors

Differential regulation of tumor necrosis factor-α-converting enzyme and angiotensin-converting enzyme by type I and II interferons in human normal and leukemic myeloid cells

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