Hypoxia induces expression of the chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8 in human dermal fibroblasts

Galindo, María; Santiago, B; Alcamí, José; Rivero, Miguel; Martín-Serrano, Juan; Pablos, José L.

doi:10.1046/j.1365-2249.2001.01412.x

Cited by 84 publications

(67 citation statements)

References 37 publications

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“…Increased MCP-1 mRNA and protein expression was reported in human dermal fibroblasts exposed to hypoxia (44), and human melanoma cell lines were shown to up-regulate MCP-1 mRNA and protein under anoxia/reoxygenation (45). Moreover, stimulatory effects of hypoxia on MCP-1 have been observed in ischemic rat neurons and myocardial cells (46,47).…”

Section: Discussionmentioning

confidence: 98%

Hypoxia Selectively Inhibits Monocyte Chemoattractant Protein-1 Production by Macrophages

Bosco

Puppo

Pastorino

et al. 2004

The Journal of Immunology

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Hypoxia, a local decrease in oxygen tension occurring in inflammatory and tumor lesions, modulates gene expression in macrophages. Because macrophages are important chemokine producers, we investigated the regulatory effects of hypoxia on macrophage-derived chemokines. We demonstrated that hypoxia inhibits the production of the macrophage and T lymphocyte chemotactic and activating factor, monocyte chemoattractant protein-1 (MCP-1). Exposure of mouse macrophages to low oxygen tension resulted in the down-regulation of constitutive MCP-1 mRNA expression and protein secretion. Hypoxia inhibitory effects were selective for MCP-1 because the chemokines macrophage inflammatory protein-1β (MIP-1β), RANTES, IFN-γ-inducible protein-10, and MIP-2 were not affected, and MIP-1α was induced. Hypoxia also inhibited, in a time-dependent fashion, MCP-1 up-regulation by IFN-γ and LPS. Moreover, the inhibitory action of hypoxia was exerted on human monocytic cells. MCP-1 down-regulation was associated with inhibition of gene transcription and mRNA destabilization, suggesting a dual molecular mechanism of control. Finally, we found that the triptophan catabolite picolinic acid and the iron chelator desferrioxamine, which mimic hypoxia in the induction of gene expression, differentially regulated the expression of MCP-1. This study characterizes a novel property of hypoxia as a selective inhibitor of MCP-1 production induced by different stimuli in macrophages and demonstrates that down-regulation of gene expression by hypoxia can be controlled at both transcriptional and posttranscriptional levels. Inhibition of MCP-1 may represent a negative regulatory mechanism to control macrophage-mediated leukocyte recruitment in pathological tissues.

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Section: Discussionmentioning

confidence: 98%

Hypoxia Selectively Inhibits Monocyte Chemoattractant Protein-1 Production by Macrophages

Bosco

Puppo

Pastorino

et al. 2004

The Journal of Immunology

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“…16,25 --27 On the other hand, it is also reported that hypoxia could induce MCP-1 expression in human dermal fibroblasts and hypoxic brain. 28,29 However, the mechanism behind the downregulation of MCP-1 mRNA is not clear, but the group of Safronova et al 30 suggested a histone deacetylases dependent one. They report that hypoxia induces the deacetylation of histones and therefore repression of MCP-1 mRNA transcription.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia reduces the response of human adipocytes towards TNFα resulting in reduced NF-κB signaling and MCP-1 secretion

et al. 2011

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OBJECTIVE: Obesity is associated with adipose tissue hypoxia, and is thought to be linked to the chronic low-grade inflammation of adipose tissue, although the precise mechanism has remained unclear. In this study, we investigated the effect of a prominent hypoxia on human primary adipocyte secretion and tumor necrosis factor alpha (TNFa)-induced nuclear factor-kB (NF-kB) signaling. RESULTS: Using cytokine array and ELISA analysis, we compared the secretion patterns of normoxic and hypoxic (1% O 2 ) adipocytes and observed various alterations in adipokine release. We could reproduce known alterations like an induction of interleukin (IL)-6, vascular endothelial growth factor, leptin and a reduction in adiponectin release under hypoxia. Interestingly, we observed a significant reduction in the secretion of macrophage chemotactic protein (MCP)-1 and other NF-kB-related genes, such as growth-regulated oncogene-a, eotaxin and soluble TNF-Receptor1 (TNF-R1) under hypoxia. TNFa stimulation of hypoxic adipocytes resulted in a significantly reduced phosphorylation of NF-kB and its inhibitor IkBa compared with normoxic cells. Furthermore, chronic treatment of hypoxic adipocytes with TNFa resulted in an expected higher secretion of the chemokines MCP-1 and IL-8, but under hypoxia, the secretion level was substantially lower than that under normoxia. This reduction in protein release was accompanied by a reduced mRNA expression of MCP-1, whereas IL-8 mRNA expression was not altered. Additionally, we observed a significantly reduced expression of the TNF-receptor TNF-R1, possibly being one cause for the reduced responsiveness of hypoxic adipocytes towards TNFa stimulation. CONCLUSION: In conclusion, human primary adipocytes show a basal and TNFa-induced reduction of MCP-1 release under hypoxia. This effect may be due to a reduced expression of TNF-R1 and therefore attenuated TNFa-induced NF-kB signaling. These observations demonstrate a reduced responsiveness of hypoxic adipocytes towards inflammatory stimuli like TNFa, which may represent an adaptation process to maintain adipose tissue function under hypoxia and inflammatory conditions.

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“…Hypoxia has been reported to upregulate MCP-1 expression in human dermal fibroblasts, 40 neonatal rat brain 41 and melanona cells. 42 The formation of MCP-1 is reduced by hypoxia in ovarian cancer cells, 43 macrophages 44,45 and human synovial fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Regulation of monocyte chemoattractant protein 1 (MCP-1) release by explants of human visceral adipose tissue

Fain

Madan

2005

Int J Obes

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BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine involved in monocyte recruitment during inflammation whose plasma level is elevated in obesity. OBJECTIVE: The present studies were designed to examine the release of MCP-1 in primary culture by explants of visceral adipose tissue from morbidly obese women. RESULTS: Most of the MCP-1 released by adipose tissue explants was derived from the nonfat cells in adipose tissue. The release of MCP-1 by adipose tissue explants was upregulated almost five-fold between 3 and 48 h of incubation. Approximately half of this upregulation was due to the release of endogenous tumor necrosis factor a (TNFa) and IL-1b based on the ability of a combination of a soluble TNFa receptor (etanercept) and a blocking antibody against IL-1b to reduce MCP-1 release. The release of MCP-1 over 48 h was unaffected by insulin or dexamethasone but significantly reduced by the combination of both agents. MCP-1 release was reduced by 60% in the presence of an inhibitor of the nuclear factor kB (NF-kB) pathway. There were no significant effects of inhibitors of p44/42 mitogen-activated protein kinase (ERK), Jun N-terminal kinase (JNK) and p38 mitogenactivated protein kinase (p38 MAPK) pathways on MCP-1 release. However, inhibition of MCP-1 release in the presence of inhibitors of both the p38 MAPK and NF-kB pathways was greater than that seen with only the NF-kB inhibitor. DISCUSSION: The present data shows that MCP-1 formation is upregulated over a 48-h incubation of primary explants of visceral adipose tissue. Half of this upregulation is dependent upon endogenous TNFa and Il-1b and involves the p38 MAPK and NF-kB pathways.

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Hypoxia induces expression of the chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8 in human dermal fibroblasts

Cited by 84 publications

References 37 publications

Hypoxia Selectively Inhibits Monocyte Chemoattractant Protein-1 Production by Macrophages

Hypoxia Selectively Inhibits Monocyte Chemoattractant Protein-1 Production by Macrophages

Hypoxia reduces the response of human adipocytes towards TNFα resulting in reduced NF-κB signaling and MCP-1 secretion

Regulation of monocyte chemoattractant protein 1 (MCP-1) release by explants of human visceral adipose tissue

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