Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes

Massonnet, Benoit; Normand, Sylvain; Moschitz, Reinhard; Delwail, Adriana; Favot, Laure; Garcia, Martine; Bourmeyster, Nicolas; Cuisset, Laurence; Grateau, Gilles; Morel, Franck; Silvain, Christine; Lecron, Jean‐Claude

doi:10.1684/ecn.2009.0162

Cited by 32 publications

(23 citation statements)

References 41 publications

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“…[1] Isoprenoid pyro- and monophosphates are substrates for the N-terminal phosphatase domain[31, 32] and these lipid phosphates are the metabolic precursors of cholesterol biosynthesis, and most importantly they are use for isoprenylation, a protein post-translational lipid modification process that is involved in the process of inflammation. [33-35] In the present study, using an advanced approach of the IBD model in IL-10(−/−) mice combined with sEH/EPHX-2 gene deficiency or sEH inhibition, we demonstrated that sEH gene deficiency or inhibition significantly ameliorated chronic active inflammation in the bowel, particularly reduced active ulcer formation, trnasmural inflammation and inflammatory cell infiltration.…”

Section: Discussionmentioning

confidence: 50%

Soluble Epoxide Hydrolase Gene Deficiency or Inhibition Attenuates Chronic Active Inflammatory Bowel Disease in IL-10(−/−) Mice

et al. 2012

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Background Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids (DHETs). Thus, targeting sEH would be important for inflammation. Aims To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(−/−) mice. Methods Either the small molecule sEH inhibitor trans/-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) or sEH knockout mice were used in combination with IL-10(−/−) mice. t-AUCB was administered to mice in drinking fluid. Extensive histopathologic, immunochemical and biochemical analyses were performed to evaluate effect of sEH inhibition or deficiency on chronic active inflammation and related mechanism in the bowel. Results Compared to IL-10 (−/−) mice, sEH inhibition or sEH deficiency in IL-10(−/−) mice resulted in significantly lower incidence of active ulcer formation and transmural inflammation, along with a significant decrease in myeloperoxidase-labeled neutrophil infiltration in the inflamed bowel. The levels of IFN-γ, TNF-α, and MCP-1, as well VCAM-1 and NF-kB/IKK-α signals were significantly decreased as compared to control animals. Moreover, an eicosanoid profile analysis revealed a significant increase in the ratio of EETs/DHET and EpOME/DiOME, and a slightly down-regulation of inflammatory mediators LTB4 and 5-HETE. Conclusion These results indicate that sEH gene deficiency or inhibition reduces inflammatory activities in the IL-10 (−/−) mouse model of IBD, and that sEH inhibitor could be a highly potential in the treatment of IBD.

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Section: Discussionmentioning

confidence: 50%

Soluble Epoxide Hydrolase Gene Deficiency or Inhibition Attenuates Chronic Active Inflammatory Bowel Disease in IL-10(−/−) Mice

et al. 2012

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“…The last cytokine analysed, IL-1β, is an important protein that mediates many of the damaging consequences of inflammatory process synergies with other pro-inflammatory cytokines such as IL-6 and IL-12, allowing the adaptive immune response to feed-back and amplify innate immunity [ 27 ]. In this respect, it has been shown that pharmacological inhibitors of the mevalonate pathway activate pro-IL-1β processing and IL-1β release by human monocytes [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Lovastatin Dose-Dependently Potentiates the Pro-inflammatory Activity of Lipopolysaccharide Both In Vitro and In Vivo

Zanin

Marcuzzi

Kleiner

et al. 2013

J. of Cardiovasc. Trans. Res.

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Since contradictory findings have been reported on potential effects of statins in modulating the inflammatory response, we have analysed the biological activity of lovastatin both in vitro using the Raw 264.7 murine macrophagic cell line and in vivo using BALB/c mice. When added to Raw 264.7 cells in combination with lipopolysaccharide, lovastatin significantly potentiated the release of interleukin-1β, interleukin-6 and interleukin-12 with respect to lipopolysaccharide alone and showed an additive effect on the release of nitric oxide. Similarly, when lovastatin was intraperitoneally administrated to BALB/c mice, it did not induce any pro-inflammatory effect when used alone, but it significantly potentiated the pro-inflammatory activity of lipopolysaccharide, in terms of number of intraperitoneal cells and serum levels of serum amyloid A, interleukin-1β, interleukin-6 and interleukin-12. A potential clinical implication of our study is that lovastatin might exert a pro-inflammatory activity in subjects affected by inflammatory processes, with clinically evident or subclinical infections.

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“…In vitro models of MKD involve treatment of cells with statins (HMG‐CoA reductase inhibitor), nitrogen‐containing bisphosphonates (inhibitors of farnesyl diphosphate synthase 10 ) or specific inhibitors of geranylgeranyltransferase I such as GGTI‐298 11 to mimic the block in protein prenylation that is assumed to occur in cells deficient in MVK. These inhibitors predispose cells to increased inflammasome activity and enhanced caspase‐1‐mediated cleavage of pro‐interleukin (IL)‐1β, 9 , 12 , 13 , 14 , 15 , 16 , 17 , 18 a characteristic feature of MKD.…”

Section: Introductionmentioning

confidence: 99%

Mevalonate kinase deficiency leads to decreased prenylation of Rab GTPases

et al. 2016

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Mevalonate kinase deficiency (MKD) is caused by mutations in a key enzyme of the mevalonate–cholesterol biosynthesis pathway, leading to recurrent autoinflammatory disease characterised by enhanced release of interleukin-1β (IL-1β). It is currently believed that the inflammatory phenotype of MKD is triggered by temperature-sensitive loss of mevalonate kinase activity and reduced biosynthesis of isoprenoid lipids required for the prenylation of small GTPase proteins. However, previous studies have not clearly shown any change in protein prenylation in patient cells under normal conditions. With lymphoblast cell lines from two compound heterozygous MKD patients, we used a highly sensitive in vitro prenylation assay, together with quantitative mass spectrometry, to reveal a subtle accumulation of unprenylated Rab GTPases in cells cultured for 3 days or more at 40 °C compared with 37 °C. This included a 200% increase in unprenylated Rab7A, Rab14 and Rab1A. Inhibition of sterol regulatory element-binding protein (SREBP) activation by fatostatin led to more pronounced accumulation of unprenylated Rab proteins in MKD cells but not parent cells, suggesting that cultured MKD cells may partially overcome the loss of isoprenoid lipids by SREBP-mediated upregulation of enzymes required for isoprenoid biosynthesis. Furthermore, while inhibition of Rho/Rac/Rap prenylation promoted the release of IL-1β, specific inhibition of Rab prenylation by NE10790 had no effect in human peripheral blood mononuclear cells or human THP-1 monocytic cells. These studies demonstrate for the first time that mutations in mevalonate kinase can lead to a mild, temperature-induced defect in the prenylation of small GTPases, but that loss of prenylated Rab GTPases is not the cause of enhanced IL-1β release in MKD.

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Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes

Cited by 32 publications

References 41 publications

Soluble Epoxide Hydrolase Gene Deficiency or Inhibition Attenuates Chronic Active Inflammatory Bowel Disease in IL-10(−/−) Mice

Soluble Epoxide Hydrolase Gene Deficiency or Inhibition Attenuates Chronic Active Inflammatory Bowel Disease in IL-10(−/−) Mice

Lovastatin Dose-Dependently Potentiates the Pro-inflammatory Activity of Lipopolysaccharide Both In Vitro and In Vivo

Mevalonate kinase deficiency leads to decreased prenylation of Rab GTPases

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