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Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response
Open accessAbstract
The local production of proinflammatory cytokines mediates the host response to inflammation, infection, and injury, whereas an overexpression of these mediators can injure or kill the host. Recently, we identified a class of multivalent guanylhydrazone compounds that are effective inhibitors of proinflammatory cytokine synthesis in monocytes/macrophages. The structure of one such cationic molecule suggested a molecular mimicry with spermine, a ubiquitous endogenous biogenic amine that increases significantly at sites of inflammation and infection. Here, we addressed the hypothesis that spermine might counterregulate the innate immune response by downregulating the synthesis of potentially injurious cytokines. When spermine was added to cultures of human peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), it effectively inhibited the synthesis of the proinflammatory cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, MIP-1alpha, and MIP-1beta. The inhibition of cytokine synthesis was specific and reversible, with significant inhibition of TNF synthesis occurring even when spermine was added after LPS. The mechanism of spermine-mediated cytokine suppression was posttranscriptional and independent of polyamine oxidase activity. Local administration of spermine in vivo protected mice against the development of acute footpad inflammation induced by carrageenan. These results identify a distinct molecular counterregulatory role for spermine in downregulating the monocyte proinflammatory cytokine response.
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“Extraneous spermine is taken up by monocytes and macrophages and selectively inhibits the LPS-induced expression of pro-inflammatory cytokines (M. Zhang et al., 1999; 1997).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as M. Zhang et al., 1997
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“spermine administration exhibits protective anti-inflammatory effects in mouse models of both localized and systemic inflammation (Steege et al., 1999; M. Zhang et al., 1997; S. Zhu et al., 2009).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as M. Zhang et al., 1997
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Metadata
- Authors
- Zhang, M., Caragine, T., Wang, H., Cohen, P. S., Botchkina, G., Soda, K., Bianchi, M., Ulrich, P., Cerami, A., Sherry, B., & Tracey, K. J.
- Affiliations
- North Shore University Hospital (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 1997-05-19
- Volume
- 185
- Issue
- 10
- Pages
- 1759-1768
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2196317
- OpenAlex
- W2147886921
- Cited by
- 317
- References
- 65
- Citations by year
- 2026: 3 · 2025: 17 · 2024: 11 · 2023: 16 · 2022: 24 · 2021: 18 · 2020: 18 · 2019: 15 · 2018: 11 · 2017: 11 · 2016: 7 · 2015: 6 · 2014: 12 · 2013: 9 · 2012: 11
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- spermine, inflammatory cytokines, cytokine synthesis inhibition, monocytes, macrophages, lipopolysaccharide stimulation, TNF-α, interleukin-1, interleukin-6, MIP-1α, MIP-1β, innate immune response, counterregulation, carrageenan-induced inflammation, polyamines, post-transcriptional regulation
- MeSH terms
- Animals, Carrageenan, Cell Line, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Female, Homeostasis, Humans, Inflammation, Interleukin-1, Kinetics, Lipopolysaccharides, Macrophages, Mice, Inbred C3H, Monocytes, Spermine, Tumor Necrosis Factor-alpha, Interleukin-6, Cytokines, Macrophage Inflammatory Proteins, Mice, Chemokine CCL3, Chemokine CCL4
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