Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow‐derived macrophages by TH 1 and TH 2 cytokines
Abstract
Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the amino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline. NO is important in the bactericidal and cytotoxic activities of macrophages. An equivalent functional role of arginase and its products is not known. We tested the induction of arginase in bone marrow-derived macrophages by endogenous mediators that are known to induce NO synthase, such as interferon-gamma (IFN-gamma), or suppress the induction of this enzyme, such as interleukin (IL)-4, IL-10, and prostaglandin E2 (PGE2). We find that PGE2 and the TH2 cytokines IL-4 and IL-10 are potent inducers of arginase. In contrast, the TH1 cytokine IFN-gamma does not induce arginase. Simultaneous application of both types of mediators leads to reduced induction of both arginase and NO synthase. Exposure of macrophage cultures to inducers of NO synthase exhausts their ability to respond subsequently to inducers of arginase. Conversely, exposure of the cells to inducers of arginase exhausts their ability to respond subsequently to inducers of NO synthase. The results are consistent with a competition of both enzymes for their substrate, L-arginine, with a reciprocal inhibition in the induction of both enzymes, or a combination of both phenomena. The enzymes NO synthase and arginase appear to define two alternate functional states of macrophages, induced by TH1 and TH2 cytokines, respectively.
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ARG1 in myeloid cells mainly functions as an enzyme to hydrolyze arginine to produce ornithine as part of the urea cycle, which promotes tissue repair through generation of polyamines and collagens, and reduces nitric oxide production from inducible nitric oxide synthase through decreasing intracellular arginine availability.
“ARG1 in myeloid cells mainly functions as an enzyme to hydrolyze arginine to produce ornithine as part of the urea cycle, which both promotes tissue repair through generation of polyamines and collagens, and also reduces nitric oxide production from inducible nitric oxide synthase through decreasing intracellular arginine availability (76–78).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [78]
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- Authors
- Modolell, M., Corraliza, I. M., Link, F., Soler, G., & Eichmann, K.
- Affiliations
- Max Planck Society (DE)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- Universidad de Extremadura (ES)
- Corresponding author
- Modolell, Manuel
- ORCID
- Soler, Germán
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 1995-04
- Volume
- 25
- Issue
- 4
- Pages
- 1101-1104
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W1984188855
- Cited by
- 554
- References
- 28
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 15 · 2023: 12 · 2022: 11 · 2021: 16 · 2020: 12 · 2019: 24 · 2018: 17 · 2017: 23 · 2016: 13 · 2015: 20 · 2014: 37 · 2013: 21 · 2012: 22
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- nitric oxide synthase, arginase, macrophages, bone marrow-derived macrophages, Th1 cytokines, Th2 cytokines, interferon-gamma, IL-4, IL-10, prostaglandin E2, L-arginine, substrate competition, macrophage activation, lipopolysaccharide
- MeSH terms
- Amino Acid Oxidoreductases, Animals, Arginase, Bone Marrow, Cells, Cultured, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, CD4-Positive T-Lymphocytes, Gene Expression Regulation, Enzymologic, T-Lymphocyte Subsets, Cytokines, Nitric Oxide Synthase, Mice
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