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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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InfluentialIron at the interface of immunity and infection
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BackgroundColleoni, F., Padmanabhan, N., Yung, H.-W., Watson, E. D., Cetin, I., Tissot van Patot, M. C., Burton, G. J., & Murray, A. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055194 · Cited by 128
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“Additionally, HIF-1α is differentially expressed in M1- and M2-polarized macrophages [59] and is a transcriptional activator of iNOS (M1 gene) expression [60, 61].”
BackgroundNitric Oxide in Liver Diseases
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“Intracellular iron plays a role in regulating gene expression at both translational and transcriptional levels (13, 16, 22, 30, 36, 41, 44, 45, 52).”
BackgroundJantsch, J., Wiese, M., Schödel, J., Castiglione, K., Gläsner, J., Kolbe, S., Mole, D., Schleicher, U., Eckardt, K.-U., Hensel, M., et al. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.1210683 · Cited by 108
“Second, we analyzed whether HIF1 binds to the known HRE in the Nos2 promoter [44].”
BackgroundPathways for the regulation of interferon-γ-inducible genes by iron in human monocytic cells
Oexle, H., Kaser, A., Möst, J., Bellmann-Weiler, R., Werner, E. R., Werner-Felmayer, G., & Weiss, G. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0802420 · Cited by 108
“This could be referred to as direct effects of the metal toward the binding activity of the transcription factors, as shown for NF-IL-6 or hypoxia-inducible factor with the iNOS promoter [6, 21, 28], or a result of catalyzation of hydroxyl radical formation by iron with subsequent changes in transcription factor bindi…”
Illsley, N. P., Caniggia, I., & Zamudio, S. (2010) · The International Journal of Developmental Biology · doi:10.1387/ijdb.082798ni · Cited by 107
“…mechanism (Coulet et al., 2003; Gao et al., 2005; Hellwig-Burgel et al., 2005; Land and Rae, 2005; Lu et al., 2006; Matrone et al., 2004; Melillo et al., 1997; Min et al., 2006; Semenza et al., 1997), thus increasing the production of NO at the same time that oxygen concentration is…”
BackgroundWang, X., Zalcenstein, A., & Oren, M. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401181 · Cited by 107
Lu, D., Liou, H., Tang, C., & Fu, W. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.06.038 · Cited by 107
Macrophage iron homeostasis and polarization in the context of cancer
Jung, M., Mertens, C., & Brüne, B. (2014) · Immunobiology · doi:10.1016/j.imbio.2014.09.011 · Cited by 105
Transcriptome of Hypoxic Immature Dendritic Cells: Modulation of Chemokine/Receptor Expression
Ricciardi, A., Elia, A. R., Cappello, P., Puppo, M., Vanni, C., Fardin, P., Eva, A., Munroe, D. J., Wu, X., Giovarelli, M., et al. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-07-0391 · Cited by 102
“erythropoietin (22), or it may require the collaboration of other transcription factors, as in the case of inducible nitric oxide synthase (20, 21, 50).”
BackgroundSelf-citationRole of Ceruloplasmin in Macrophage Iron Efflux during Hypoxia
Sarkar, J., Seshadri, V., Tripoulas, N. A., Ketterer, M. E., & Fox, P. L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304926200 · Cited by 101
Ser, H., Mutalib, N. A., Yin, W., Chan, K., Goh, B. H., & Lee, L. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.01398 · Cited by 100
“SI value was calculated by dividing IC50 of cancer cell line with IC50 value of normal cell line.”
BackgroundMethodHan, J.-Y., Oh, S. H., Morgillo, F., Myers, J. N., Kim, E., Hong, W. K., & Lee, H.-Y. (2005) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/dji251 · Cited by 99
Microtubule Disruption Utilizes an NFκB-dependent Pathway to Stabilize HIF-1α Protein
Jung, Y., Isaacs, J. S., Lee, S., Trepel, J. B., & Neckers, L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209804200 · Cited by 99
Date, T., Mochizuki, S., Belanger, A. J., Yamakawa, M., Luo, Z., Vincent, K. A., Cheng, S. H., Gregory, R. J., & Jiang, C. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00374.2004 · Cited by 98
“It is conceivable that upregulation of Glut-1, Glut-4, and iNOS is mediated by HIF because they are known HIF-1 target genes (19, 25, 32).”
BackgroundDachs, G. U., & Chaplin, D. J. (1998) · Seminars in Radiation Oncology · doi:10.1016/s1053-4296(98)80046-5 · Cited by 94
Hypoxia Selectively Inhibits Monocyte Chemoattractant Protein-1 Production by Macrophages
Bosco, M. C., Puppo, M., Pastorino, S., Mi, Z., Melillo, G., Massazza, S., Rapisarda, A., & Varesio, L. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.3.1681 · Cited by 93
“For iNOS detection, the cDNA probe specific for mouse M -inducible NOS was used (28).”
BackgroundMethodInfluentialSelf-citationRole of nucleolin in posttranscriptional control of MMP-9 expression
Fähling, M., Steege, A., Perlewitz, A., Nafz, B., Mrowka, R., Persson, P. B., & Thiele, B. J. (2005) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/j.bbaexp.2005.08.005 · Cited by 93
“Consequently, iron-chelators as desferrioxamine (DFO) or 2,2-Dipyridyl are used to mimic hypoxia in the study of hypoxia response pathways [22–24].”
Background‘Ride on the ferrous wheel’ – The cycle of iron in macrophages in health and disease
Nairz, M., Schroll, A., Demetz, E., Tancevski, I., Theurl, I., & Weiss, G. (2015) · Immunobiology · doi:10.1016/j.imbio.2014.09.010 · Cited by 89
The impact of metal availability on immune function during infection
Monteith, A. J., & Skaar, E. P. (2021) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2021.08.004 · Cited by 83
An Inducible Nitric-oxide Synthase (NOS)-associated Protein Inhibits NOS Dimerization and Activity
Ratovitski, E. A., Bao, C., Quick, R. A., McMillan, A., Kozlovsky, C., & Lowenstein, C. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30250 · Cited by 86
p53 Activation by Nitric Oxide Involves Down-regulation of Mdm2
Wang, X., Michael, D., de MURCIA, G., & Oren, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112068200 · Cited by 84
Matrone, C., Pignataro, G., Molinaro, P., Irace, C., Scorziello, A., Renzo, G. F. D., & Annunziato, L. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02483.x · Cited by 81
“…in the areas under consideration, after pMCAO is reminiscent of HIF-1-induced iNOS activation under hypoxic and non- hypoxic conditions in cardiac myocytes (Jung et al. 2000), pulmonary artery endothelial cells (Palmer et al. 1998) and in the macrophage cell line ANA-1 (Melillo et al. 1997).”
BackgroundMethodInfluentialUnderstanding How Minerals Contribute to Optimal Immune Function
Ştefanache, A., Lungu, I. I., Butnariu, I.-A., Călin, G., Guțu, C., Marcu, C., Grierosu, C., Goroftei, E. R. B., Duceac, L.-D., Dabija, M. G., et al. (2023) · Journal of Immunology Research · doi:10.1155/2023/3355733 · Cited by 99
“Similar to this, iron chelation with DFO stimulates HIF-1, which increases the transactivation of the Nos2 gene [135].”
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Effects of Tetrahydrobiopterin on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure
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“described (33) with the exception that, following UTP incorporation, the nuclei”
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Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury
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“Since iNOS is a downstream target of HIF-1 (33, 34, 38) that has been implicated as a critical inflammatory and injurious mediator of I/R-induced gut barrier failure (17, 50, 54), we asked whether HIF-1 modulated iNOS expression during intestinal I/R injury.”
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“(35), in neuroblastoma cells, resulting in the suppression of HIF-driven VEGF transcription and to decreased VEGF production.”
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“…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…”
TXNIP Deficiency Exacerbates Endotoxic Shock via the Induction of Excessive Nitric Oxide Synthesis
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Hypoxia-inducible factor 1, a master transcription factor of cellular hypoxic gene expression
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“Moreover, transcription of the iNOS gene in murine macrophages is increased through an HRE in the iNOS promoter [63,64].”
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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