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Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide.
Open accessAbstract
Escherichia coli lipopolysaccharide (LPS)-induced nitrate biosynthesis was studied in LPS-sensitive C3H/He and LPS-resistant C3H/HeJ mice. Intraperitoneal injection of 15 micrograms of LPS led to a temporary 5- to 6-fold increase in blood nitrate concentration in the C3H/He strain. Levels of nitrate excreted in the urine were also increased. In contrast, no increase was observed in the C3H/HeJ strain with LPS injections up to 175 micrograms. Furthermore, thioglycolate-elicited peritoneal macrophages from C3H/He, but not from C3H/HeJ mice, produced nitrite (60%) and nitrate (40%) when cultured with LPS (10 micrograms/ml). T-lymphocyte addition/depletion experiments showed the presence of T cells enhanced this response. However, LPS did not cause nitrite or nitrate production in cultures of spleen lymphocytes from either strain. LPS-induced nitrate synthesis was also observed with nude mice and CBA/N mice, indicating that neither functional T lymphocytes nor LPS-responsive B lymphocytes were required for the response in vivo. This was consistent with the in vitro results showing macrophages alone were competent. Mycobacterium bovis infection of C3H/He and C3H/HeJ mice resulted in a large increase in nitrate production over the course of the infection for both strains, suggesting T-lymphocyte-mediated activation of macrophages as a potent stimulus for nitrate biosynthesis. The synthesis of nitrite is significant in that it can directly participate in the endogenous formation of nitrosamines and may also be involved in some aspect of the chemistry of cytotoxicity.
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“While there are similar resting levels of nitrate (25 μM) and nitrite (1 μM) in both species, administration of LPS to mice led to as much as 1 mM nitrate/nitrite while in humans peak levels were only 50-115 μM [34, 39-42]).”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [42]
In the citing paper
“Early studies demonstrated that immune activators such as LPS and IL-2 clearly drive increases in plasma nitrate/nitrite in mice and in humans [34-42].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [42]
In the citing paper
“While there are similar resting levels of nitrate (25 μM) and nitrite (1 μM) in both species, administration of LPS to mice led to as much as 1 mM nitrate/nitrite while in humans peak levels were only 50-115 μM [34, 39-42]).”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [42]
In the citing paper
“Activation with IFNγ and LPS of murine macrophages leads to significant and rapid increases in nitrate/nitrite, reaching >10 μM in media within hours of NOS2 induction [42].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [42]
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Metadata
- Authors
- Stuehr, D. J., & Marletta, M. A.
- Affiliations
- Massachusetts Institute of Technology (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1985-11
- Volume
- 82
- Issue
- 22
- Pages
- 7738-7742
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC391409
- OpenAlex
- W1984997174
- Cited by
- 1,126
- References
- 35
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 10 · 2023: 8 · 2022: 13 · 2021: 11 · 2020: 17 · 2019: 14 · 2018: 18 · 2017: 18 · 2016: 7 · 2015: 16 · 2014: 12 · 2013: 13 · 2012: 31
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA-26731)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- nitrite, macrophages, lipopolysaccharide, Escherichia coli, C3H/He mice, C3H/HeJ mice, T cells, peritoneal macrophages, nitrosamines, cytotoxicity
- MeSH terms
- Animals, BCG Vaccine, Escherichia coli, Lipopolysaccharides, Macrophage Activation, Macrophages, Mice, Inbred BALB C, Mice, Inbred CBA, Mice, Inbred C3H, Nitrates, Nitrites, T-Lymphocytes, Mice
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