Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite
Abstract
Previous studies have shown that cytotoxic activated macrophages cause inhibition of DNA synthesis, of mitochondrial respiration, and of aconitase activity in tumor target cells. An L-arginine-dependent biochemical pathway synthesizing L-citrulline and nitrite, coupled to an effector mechanism, is now shown to cause this pattern of metabolic inhibition. Murine cytotoxic activated macrophages synthesize L-citrulline and nitrite in the presence of L-arginine but not D-arginine. L-Citrulline and nitrite biosynthesis by cytotoxic activated macrophages is inhibited by NG-monomethyl-L-arginine, which also inhibits this cytotoxic effector mechanism. This activated macrophage cytotoxic effector system is associated with L-arginine deiminase activity, and the imino nitrogen removed from the guanido group of L-arginine by the deiminase reaction subsequently undergoes oxidation to nitrite. L-Homoarginine, an alternative substrate for this deiminase, is converted to L-homocitrulline with concurrent nitrite synthesis and similar biologic effects.
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iNOS2 has been associated with immunostimulation and immunosuppression.
“iNOS2, which has been associated with immunostimulation (Hibbs et al., 1987; Murray et al., 2014; Stuehr and Nathan, 1989), as well as immunosuppression (Shi et al., 2001).”
From TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy (2020) · cites this paper as Hibbs et al., 1987
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- Authors
- Hibbs, J. B., Taintor, R. R., & Vavrin, Z.
- Affiliations
- University of Utah (US)
- Venue
- Science
- Published
- 1987-01-23
- Volume
- 235
- Issue
- 4787
- Pages
- 473-476
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2057025197
- Cited by
- 1,527
- References
- 1
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 6 · 2023: 4 · 2022: 15 · 2021: 24 · 2020: 23 · 2019: 22 · 2018: 14 · 2017: 24 · 2016: 28 · 2015: 21 · 2014: 30 · 2013: 24 · 2012: 30
- FWCI
- 17.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- macrophage cytotoxicity, citrulline, L-arginine, L-NMMA, L-homoarginine, DNA synthesis inhibition, mitochondrial respiration inhibition, aconitase inhibition, tumor target cells, macrophage activation
- MeSH terms
- Ammonia, Animals, Cells, Cultured, Citrulline, Cytotoxicity, Immunologic, Homoarginine, Hydrolases, Macrophage Activation, Macrophages, Nitrates, Nitrites, Mice
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