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Cited by 51Cancer, Lipids, and MetabolismCholesterol and Lipid MetabolismAtherosclerosis and Cardiovascular Diseases

The differential statin effect on cytokine production of monocytes or macrophages is mediated by differential geranylgeranylation-dependent Rac1 activation

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Fu, Hang, Alabdullah, Mohamad, Großmann, Julia, Spieler, Florian, Abdosh, Reem, Lutz, Veronika, Kalies, Katrin, Knöpp, Kai +10 more·2019·Cell Death & Disease
DOI 10.1038/s41419-019-2109-9PMC PMC6872739
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Abstract

Monocytes and macrophages contribute to pathogenesis of various inflammatory diseases, including auto-inflammatory diseases, cancer, sepsis, or atherosclerosis. They do so by production of cytokines, the central regulators of inflammation. Isoprenylation of small G-proteins is involved in regulation of production of some cytokines. Statins possibly affect isoprenylation-dependent cytokine production of monocytes and macrophages differentially. Thus, we compared statin-dependent cytokine production of lipopolysaccharide (LPS)-stimulated freshly isolated human monocytes and macrophages derived from monocytes by overnight differentiation. Stimulated monocytes readily produced tumor necrosis factor-α, interleukin-6, and interleukin-1β. Statins did not alter cytokine production of LPS-stimulated monocytes. In contrast, monocyte-derived macrophages prepared in the absence of statin lost the capacity to produce cytokines, whereas macrophages prepared in the presence of statin still produced cytokines. The cells expressed indistinguishable nuclear factor-kB activity, suggesting involvement of separate, statin-dependent regulation pathways. The presence of statin was necessary during the differentiation phase of the macrophages, indicating that retainment-of-function rather than costimulation was involved. Reconstitution with mevalonic acid, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate blocked the retainment effect, whereas reconstitution of cholesterol synthesis by squalene did not. Inhibition of geranylgeranylation by GGTI-298, but not inhibition of farnesylation or cholesterol synthesis, mimicked the retainment effect of the statin. Inhibition of Rac1 activation by the Rac1/TIAM1-inhibitor NSC23766 or by Rac1-siRNA (small interfering RNA) blocked the retainment effect. Consistent with this finding, macrophages differentiated in the presence of statin expressed enhanced Rac1-GTP-levels. In line with the above hypothesis that monocytes and macrophages are differentially regulated by statins, the CD14/CD16-, merTK-, CX 3 CR1-, or CD163-expression (M2-macrophage-related) correlated inversely to the cytokine production. Thus, monocytes and macrophages display differential Rac1-geranylgeranylation-dependent functional capacities, that is, statins sway monocytes and macrophages differentially.

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  • The study demonstrated that altered cholesterol homeostasis in FXS astrocytes was associated with broader changes in lipidome and inflammatory factors, which are potentially directly modulated by statins.

    “Our study demonstrated that altered cholesterol homeostasis in FXS astrocytes was associated with broader changes in lipidome and inflammatory factors, which are potentially directly modulated by statins61.”

    From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [61]

    The Discussion (page not provided) reports that statins affect inflammatory cytokine production in macrophages, supporting the possibility that statins modulate inflammatory factors. The Results (page not provided) do not examine lipidome changes, and the paper studies monocytes and macrophages rather than FXS astrocytes. The cited portion therefore supports only the inflammatory-factor aspect of the proposed modulation. (LLM, conf=0.86)

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Sorted by citations

Authors
Fu, H., Alabdullah, M., Großmann, J., Spieler, F., Abdosh, R., Lutz, V., Kalies, K., Knöpp, K., Rieckmann, M., Koch, S., Noutsias, M., Pilowski, C., Dutzmann, J., Sedding, D., Hüttelmaier, S., Umezawa, K., Werdan, K., & Loppnow, H.
Affiliations
  • University Hospital Magdeburg (DE)
  • Martin Luther University Halle-Wittenberg (DE)
  • Philipps University of Marburg (DE)
  • Aichi Medical University (JP)
Corresponding author
Loppnow, Harald
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2019-11-21
Volume
10
Issue
12
Pages
880-880
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-019-2109-9
PMC
PMC6872739
OpenAlex
W2990302499
Cited by
51
References
1
Citations by year
2026: 5 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 7 · 2021: 12 · 2020: 5
FWCI
1.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Deutscher Akademischer Austauschdienst
  • Universität Leipzig
  • Japan Society for the Promotion of Science (17K01967)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
statins, cytokine production, monocytes, macrophages, geranylgeranylation, Rac1 activation, monocyte-derived macrophages, lipopolysaccharide stimulation, TNF-α, interleukin-6, IL-1β, GGTI-298, mevalonate, farnesyl pyrophosphate, cholesterol biosynthesis
MeSH terms
Benzamides, Cell Differentiation, Humans, Macrophages, Monocytes, Cytokines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, rac1 GTP-Binding Protein, Prenylation

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