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Functional Requirement of the Hypoxia-responsive Element in the Activation of the Inducible Nitric Oxide Synthase Promoter by the Iron Chelator Desferrioxamine
Open accessAbstract
We have previously reported that a 19-base pair element of the 5'-flanking region of the inducible nitric oxide synthase (iNOS) gene containing a sequence homology to a hypoxia-responsive enhancer (iNOS-HRE) mediates picolinic acid (PA)- or hypoxia-induced activation of the iNOS promoter in interferon-gamma (IFN-gamma)-treated murine macrophages. The iron chelator desferrioxamine (DFX) induces the activity of the human erythropoietin enhancer in Hep3B cells. We have investigated the influence of DFX on the activation of the iNOS promoter and iNOS gene expression in ANA-1 macrophages. We have found that DFX induced DNA-binding activity to the hypoxia-inducible factor 1 (HIF-1) consensus sequence of the iNOS promoter and activated the iNOS-HRE in murine macrophages. These activities of DFX were associated with a synergistic induction of iNOS mRNA expression and iNOS transcription in IFN-gamma-treated ANA-1 macrophages. Functional analysis of the 5'-flanking region of the iNOS gene demonstrated that IFN-gamma plus DFX activated the full-length iNOS promoter and that the iNOS-HRE was required for DFX-induced iNOS transcriptional activity. We also investigated the role of iron metabolism in the DFX- or PA-dependent induction of HIF-1 activity and iNOS expression. We demonstrate that addition of iron sulfate completely abolished DFX or PA induction of HIF-1 binding and iNOS-HRE activation and abrogated IFN-gamma plus either DFX- or PA-induced iNOS expression. These data establish that DFX is a co-stimulus for the transcriptional activation of the iNOS gene in IFN-gamma-treated macrophages, and they provide evidence that the iNOS-HRE is required for the DFX-dependent activation of the iNOS promoter. Furthermore, our results indicate that the iNOS-HRE is a regulatory element of the iNOS promoter responsive to iron chelation.
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In the citing paper
“Thereby iron chelators antagonize a direct inhibitory effect of iron toward the expression of iNOS (Weiss et al., 1994; Melillo et al., 1997; Dlaska and Weiss, 1999).”
From Iron at the interface of immunity and infection (2014) · cites this paper as Melillo et al., 1997
In the citing paper
“In addition, high intracellular iron levels inhibit the transcription of TNF (Byrd, 1997) or other IFN-γ inducible pathways such as induction of NOS2, degradation of tryptophan or formation of neopterin in human monocytes (Melillo et al., 1997;Weiss et al., 1992Weiss et al., , 1994)).”
From Iron in infection and immunity (2020) · cites this paper as Melillo et al., 1997
In the citing paper
“Mechanistically, the latter observation can be referred to the fact that iron exerts inhibitory effects toward IFN-γ-mediated immune pathways such as the formation of TNF-α, IL-6, IL-12 MHC class II, of IDO or NOS2 (185, 187–189), whereas iron excess stimulates the formation of the macrophage de-activating cytokine IL-10 (190).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [189]
In the citing paper
“The negative effects of iron on NOS2 transcription, which can be referred to a reduced binding affinity of the transcription factors NF-IL6 (C/EBP-β) and hypoxia inducible factor 1 (HIF-1) to the NOS2 promoter (167, 189, 191), is part of a regulatory feedback loop, by which NO modulates the IRE-binding function of IRPs, thereby affecting ferritin translation and intracellular iron availability and”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [189]
In the citing paper
“Specifically, macrophage functions driven by IFN-γ are impaired when macrophages are exposed to surplus iron [138, 162, 176] largely because iron directly inhibits the binding activities of the transcription factors nuclear factor interleukin-6 (NF-IL6) and hypoxia-inducible factor (HIF)-1α [55, 153] [176].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [153]
In the citing paper
“Intracellular Fe accumulation in Mø represses IFNc receptor signaling, most likely explaining why reducing intracellular Fe content promotes IFNc-driven resistance pathways involving the induction of histocompatibility (MHC) class II, iNOS/NOS2 TNF, IL-6, or IL-12 expression [164][165][166][167].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [165]
In the citing paper
“Reduction in intracellular iron concentrations has been shown to promote the production of pro-inflammatory molecules such as TNF-α, IL-6, iNOS (nos2) or CCL-20 by activated macrophages (Weiss et al., 1994; Melillo et al., 1997; Ludwiczek et al., 2003; Oexle et al., 2003; Varesio et al., 2010), and these pathways are of importance for the control of intracellular pathogens like Salmonella (Andrews”
From Heme oxygenase 1 controls early innate immune response of macrophages to Salmonella Typhimurium infection: Heme oxygenase 1 expression affects Salmonella infection (2016) · cites this paper as Melillo et al., 1997
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Cited by
Sorted by citations
Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989
“transcription factors NF-IL6 (C/EBP-b) and hypoxia inducible factor 1 (HIF-1) to the NOS2 promoter (167, 189, 191), is part of a regulatory feedback loop, by which NO modulates the IRE-binding function of IRPs, thereby affecting ferritin translation and intracellular iron availability and linking maintenance of iron h…”
BackgroundReactive oxygen and reactive nitrogen intermediates in innate and specific immunity
Bogdan, C., Röllinghoff, M., & Diefenbach, A. (2000) · Current Opinion in Immunology · doi:10.1016/s0952-7915(99)00052-7 · Cited by 952
HIF-1α expression regulates the bactericidal capacity of phagocytes
Peyssonnaux, C., Datta, V., Cramer, T., Doedens, A. L., Theodorakis, E. A., Gallo, R. L., Hurtado‐Ziola, N., Nizet, V., & Johnson, R. S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23865 · Cited by 715
Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway
Isaacs, J. S., Jung, Y.-J., Mimnaugh, E. G., Martinez, A., Cuttitta, F., & Neckers, L. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204733200 · Cited by 663
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641
“HIF-1 mediates transcriptional activation of the genes encoding heme oxygenase-1 (HO-1) (188), inducible nitric oxide synthase (iNOS) (226), and angiotensin converting enzyme (ACE) (381).”
Background
Metadata
- Authors
- Melillo, G., Taylor, L. S., Brooks, A., Musso, T., Cox, G. W., & Varesio, L.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Melillo, Giovanni
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-05
- Volume
- 272
- Issue
- 18
- Pages
- 12236-12243
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2011537701
- Cited by
- 201
- References
- 50
- Citations by year
- 2025: 5 · 2023: 2 · 2022: 6 · 2021: 3 · 2020: 8 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 6 · 2014: 7 · 2013: 9 · 2012: 7
- FWCI
- 6.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- inducible nitric oxide synthase, hypoxia response element, deferoxamine, iron chelation, HIF-1, iNOS promoter, interferon-gamma, macrophages, iron metabolism, transcriptional activation, picolinic acid, iron sulfate
- MeSH terms
- Animals, Base Sequence, Cell Line, Cell Nucleus, Deferoxamine, Enzyme Induction, Ferrous Compounds, Humans, Interferon-gamma, Macrophages, Mice, Inbred C57BL, Promoter Regions, Genetic, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Transfection, Cell Hypoxia, Gene Expression Regulation, Enzymologic, Consensus Sequence, Nitric Oxide Synthase, Mice
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