ArticleCell death & disease2019
The differential statin effect on cytokine production of monocytes or macrophages is mediated by differential geranylgeranylation-dependent Rac1 activation.
Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- Blood pressure-lowering activity of statins: a systematic literature review and meta-analysis of placebo-randomized controlled trials.European journal of clinical pharmacology · 2020Pooled it
- Adipocyte-derived exosomal miR-27a-3p promotes macrophage M1 polarization via HACE1/RAC1/STAT3 axis to exacerbate the progression of childhood asthma.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Statins and Myasthenia Gravis: Clinical Implications and Pathogenesis.International journal of molecular sciences · 2026Review
- Protein farnesylation: from molecular mechanisms to therapeutic targeting in cancer, aging, and beyond.Frontiers in pharmacology · 2026Review
- Molecular and Immunomodulatory Mechanisms of Statins in Inflammation and Cancer Therapeutics with Emphasis on the NF-κB, NLRP3 Inflammasome, and Cytokine Regulatory Axes.International journal of molecular sciences · 2025Review
- Anti-inflammatory effect of fluvastatin on polarized macrophages and its dependence on the mevalonate pathway.Scientific reports · 2025Article
- Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation.Biology direct · 2025Article
- Pravastatin prevents colitis-associated carcinogenesis by reducing CX3CR1Scientific reports · 2024Article
- Mitigating Vascular Inflammation by Mimicking AIBP Mechanisms: A New Therapeutic End for Atherosclerotic Cardiovascular Disease.International journal of molecular sciences · 2024Review
- Mononuclear phagocyte morphological response to chemoattractants is dependent on geranylgeranyl pyrophosphate.American journal of physiology. Endocrinology and metabolism · 2024Article
- In Vitro Targeted Delivery of Simvastatin and Niacin to Macrophages Using Mannan-Grafted Magnetite Nanoparticles.ACS omega · 2024Article
- Article
- Mechanisms and treatment of atherosclerosis: focus on macrophages.Frontiers in immunology · 2024Review
- Interfering with Rac1-activation during neonatal monocyte-macrophage differentiation influences the inflammatory responses of M1 macrophages.Cell death & disease · 2023Article
- An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis.Communications biology · 2023Article
- Statins mediate anti- and pro-tumourigenic functions by remodelling the tumour microenvironment.Disease models & mechanisms · 2022Article
- Cholesterol and saturated fatty acids synergistically promote the malignant progression of prostate cancer.Neoplasia (New York, N.Y.) · 2022Article
- Cardiovascular risk factors: The effects of ageing and smoking on the immune system, an observational clinical study.Frontiers in immunology · 2022Observational
- Article
- Statins and Bempedoic Acid: Different Actions of Cholesterol Inhibitors on Macrophage Activation.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
18 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.