Hydroxymethylglutaryl-coenzyme A reductase inhibition stimulates caspase-1 activity and Th1-cytokine release in peripheral blood mononuclear cells

Montero, M. Teresa; Hernández, Osvaldo; Suárez, Yajaira; Matilla, Joaquı́n; Ferruelo, Antonio; Martı́nez-Botas, Javier; Gómez-Coronado, Diego; Lasunción, Miguel A.

doi:10.1016/s0021-9150(00)00417-2

Cited by 91 publications

(76 citation statements)

References 60 publications

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“…PBMCs, stimulated with M tuberculosis in the presence of lovastatin, reportedly secreted more IFN␥, IL-1␤, and IL-18 (17). Using a combination of T cellstimulating monoclonal antibodies against CD2 and CD28, we found that lovastatin caused a 9-fold increase in IL-1␤ secretion by normal PBMCs, although a similar effect on IFN␥ secretion did not reach significance.…”

Section: Discussionmentioning

confidence: 73%

“…From previous experiments (17), it had become clear that mevalonic acid could abort the increase in cytokine secretion, mediated by lovastatin. To investigate whether this was an effect of mevalonic acid per se or one of its downstream metabolites, we studied the ability of FOH and GGOH to correct this increased secretion.…”

Section: Lack Of Isoprenoids Raises Il-1␤ In Hids 2797mentioning

confidence: 99%

“…Statins enhance endothelial expression of cellular adhesion molecules (16). Interestingly, the secretion of IL-1␤, IFN␥, and IL-18 by PBMCs stimulated ex vivo with inactivated Mycobacterium tuberculosis is augmented greatly by the inhibition of isoprenoid biosynthesis with statins (17). The increased cytokine secretion appeared to be Th1-induced and to be due to lack of isoprenoids, since the addition of mevalonic acid reduced cytokine secretion to control levels.…”

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confidence: 99%

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Lack of isoprenoid products raises ex vivo interleukin‐1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome

Frenkel

Rijkers

Mandey

et al. 2002

Arthritis & Rheumatism

159

109

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Objective. To investigate whether the increased interleukin-1␤ (IL-1␤) secretion in hyperimmunoglobulinemia D and periodic fever syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds.Methods. The effects of lovastatin and farnesol (FOH), geranylgeraniol (GGOH), and mevalonate on peripheral blood mononuclear cells (PBMCs) from 8 patients with MK deficiency and from 13 controls were studied. Lovastatin inhibits isoprenoid biosynthesis by reducing the production of mevalonate. FOH and GGOH restore isoprenoid biosynthesis downstream from MK. Culture supernatants were collected for cytokine analysis 48 hours after stimulation with monoclonal antibodies against CD2 ؉ CD28.Results. Lovastatin induced a 15-fold rise in IL-1␤ secretion by normal anti-CD2 ؉ CD28-stimulated cells (P < 0.001). This effect could be countered by mevalonate and, to a lesser extent, by FOH and GGOH. In the absence of lovastatin, mevalonate did not change IL-1␤ secretion. Stimulated MKdeficient cells secreted 9-fold more IL-1␤ than control PBMCs (P < 0.005), rising 2.4-fold in the presence of lovastatin. The effect of lovastatin on IL-1␤ secretion was reduced by mevalonate, FOH, and GGOH. Isoprenoid biosynthesis in PBMCs from patients was impaired due to the endogenous MK deficiency. Bypassing this defect with FOH, in the absence of lovastatin, led to a 62% reduction (P < 0.02) in IL-1␤ secretion by these cells.Conclusion. In this model, shortage of isoprenoid end products contributes to increased IL-1␤ secretion by MK-deficient PBMCs, whereas excess mevalonate does not.

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Section: Discussionmentioning

confidence: 73%

Section: Lack Of Isoprenoids Raises Il-1␤ In Hids 2797mentioning

confidence: 99%

mentioning

confidence: 99%

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Lack of isoprenoid products raises ex vivo interleukin‐1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome

Frenkel

Rijkers

Mandey

et al. 2002

Arthritis & Rheumatism

159

109

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“…For example, statins can function as anti-inflammatory agents, antioxidants, immunomodulators, and angiogenic agents depending on the non-transformed cell type. [131][132][133][134][135][136][137][138][139] In addition, statins can block vascular smooth muscle cell proliferation as well as signal endothelial cell survival and progenitor cell expansion. [140][141][142][143][144] These results underscore the cell type-dependent effects of statins as well as the pleiotropic effects of these agents.…”

Section: Molecular Mechanism Of Statin-induced Apoptosismentioning

confidence: 99%

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

et al. 2002

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The statin family of drugs target HMG-CoA reductase, the ratelimiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.

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“…13,14 However, statins are not simply anti-inflammatory and a series of findings, including our own, have demonstrated the paradoxical statin-induced increase in IL1b secretion as a result of decreased protein prenylation in immune cells such as macrophages. [15][16][17][18][19][20] …”

Section: Statins Cholesterol and Inflammationmentioning

confidence: 99%

Is immunity a mechanism contributing to statin-induced diabetes?

Henriksbo¹,

Schertzer

2015

Adipocyte

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Hydroxymethylglutaryl-coenzyme A reductase inhibition stimulates caspase-1 activity and Th1-cytokine release in peripheral blood mononuclear cells

Cited by 91 publications

References 60 publications

Lack of isoprenoid products raises ex vivo interleukin‐1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome

Lack of isoprenoid products raises ex vivo interleukin‐1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

Is immunity a mechanism contributing to statin-induced diabetes?

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