The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency

Pontillo, Alessandra; Paoluzzi, Elisa; Crovella, Sérgio

doi:10.1038/ejhg.2010.9

Cited by 49 publications

(34 citation statements)

References 14 publications

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“…In pure cultures of gd T cells, zoledronate was extremely toxic. Addition of GGPP, which can restore protein prenylation despite inhibition of mevalonate metabolism (1,29,30), eliminated zoledronate toxicity. Further supplementation with IL-18 was sufficient to enable a vigorous proliferative response of gd T cells in the absence of any other accessory cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although upstream accumulation of IPP during N-BP-mediated FPP synthase inhibition provides Ag for the specific stimulation of gd T cells, the downstream depletion of FPP and geranylgeranyl pyrophosphate (GGPP) was shown to generate cell stress and to translate into caspase-1-dependent inflammatory responses, both in vitro and in vivo (3,(28)(29)(30). IL-18, which is a stress-related, caspase-1-processed cytokine (31), was implicated in zoledronateinduced NK cell and gd T cell activation (29) and was shown to costimulate zoledronate-induced, IL-2-driven gd T cell expansion (32).…”

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confidence: 99%

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Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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The potent nitrogen-containing bisphosphonate zoledronate inhibits farnesyl pyrophosphate synthase, a key enzyme of the mevalonate pathway that is often hyperactive in malignant cells. Zoledronate activates human Vγ9Vδ2 T cells, which are immune sentinels of cell stress and tumors, through upstream accumulation of the cognate Ag isopentenyl pyrophosphate. IL-18 was shown to enhance zoledronate-induced γδ T cell activation. Although monocytes have been considered important accessory cells that provide the Ag isopentenyl pyrophosphate, CD56brightCD11c+ NK cells were postulated to mediate the costimulatory effects of IL-18. We report in this article that downstream depletion of geranylgeranyl pyrophosphate (GGPP), which is required for protein prenylation, caused cell stress in monocytes, followed by caspase-1–mediated maturation and release of IL-18, which, in turn, induced γδ T cell CCL2. Likewise, zoledronate caused a substantial delay in γδ T cell expansion, which could be skipped by GGPP supplementation. Moreover, repletion of GGPP, which prevented acute zoledronate toxicity, and supplementation with IL-18, which strongly upregulated IL-2Rα (CD25) and favored the central memory phenotype, were sufficient to enable zoledronate-induced expansion of highly purified γδ T cells, even when starting cell numbers were as low as 104 γδ T cells. Our study reveals essential components of γδ T cell activation and indicates that exogenous IL-18, which can directly costimulate γδ T cells, eliminates the need for any accessory cells. Our findings will facilitate the generation of robust γδ T cells from small blood or tissue samples for cancer immunotherapy and immune-monitoring purposes.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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“…45 In MKD, the enzyme is inactive because of mutations of the encoding gene. Lack of mevalonate kinase, the second enzyme of the mevalonate pathway ( Figure 1B), results in GGPP deprivation followed by For personal use only.…”

Section: Discussionmentioning

confidence: 99%

DC-like cell-dependent activation of human natural killer cells by the bisphosphonate zoledronic acid is regulated by γδ T lymphocytes

Nussbaumer

Gruenbacher

Gander

et al. 2011

Blood

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Bisphosphonates are mainly used for the inhibition of osteoclast-mediated bone resorption but also have been shown to induce ␥␦ T-cell activation. Using IL-2-primed cultures of CD56 ؉ peripheral blood mononuclear cells, we show here that zoledronic acid (zoledronate) could induce IFN-␥ production not only in ␥␦ T lymphocytes but, surprisingly, also in natural killer (NK) cells in a manner that depended on antigen-presenting cells, which share properties of inflammatory monocytes and dendritic cells (DCs; here referred to as DC-like cells). In the presence of ␥␦ T lymphocytes, DC-like cells were rapidly eliminated, and NK cell IFN-␥ production was silenced. Conversely, in the absence of ␥␦ T lymphocytes, DClike cells were spared, allowing NK cell IFN-␥ production to proceed. ␥␦ T cellindependent NK cell activation in response to zoledronate was because of downstream depletion of endogenous prenyl pyrophosphates and subsequent caspase-1 activation in DC-like cells, which then provide mature IL-18 and IL-1␤ for the activation of IL-2-primed NK cells. Pharmacologic inhibition of caspase-1 almost abolished IFN-␥ production in NK cells and ␥␦ T lymphocytes, indicating that caspase-1-mediated cytokine maturation is the crucial mechanism underlying innate lymphocyte activation in response to zoledronate. (Blood. 2011; 118(10):2743-2751) IntroductionThe bisphosphonates zoledronate and pamidronate are approved by the Food and Drug Administration for the treatment of metastatic bone disease of hematopoietic tumors such as multiple myeloma 1,2 and nonhematopoietic tumors such as breast 3 and prostate cancer. 4 Inhibition of farnesyl pyrophosphate synthase, an enzyme of the mevalonate pathway for cholesterol biosynthesis and protein prenylation, 5 is one important mechanism for bisphosphonate effects on bone resorption. 1,4 Inhibition of farnesyl pyrophosphate synthase leads to farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) deprivation and the subsequent failure to perform farnesylation and geranylgeranylation of small guanosine triphosphatases (GTPases) of the RAS superfamily. Inhibition of RAS signaling because of the disruption of membrane anchoring of these GTPases eventually prevents osteoclast-mediated bone resorption. 6,7 In addition to their effects on bone metabolism, bisphosphonates may have immunomodulatory effects, particularly on the innate immune system. [8][9][10][11] Evidence for the stimulation of ␥␦ T lymphocytes by bisphosphonates was obtained when expansion of ␥␦ T lymphocytes was observed in patients who had acute-phase reactions after their first treatment with pamidronate. 12 Inhibition of FPP synthase by bisphosphonates leads to the accumulation of isopentenyl pyrophosphate that can be specifically recognized by ␥␦ T lymphocytes expressing the V␦2V␥9 T-cell receptors. 13 Hematopoietic tumor cell lines such as Daudi (Burkitt lymphoma) or RPMI 8226 (myeloma) are specifically recognized and lysed by these ␥␦ T lymphocytes in vitro. 14,15 Moreover, ␥␦ T lymphocytes have recently been...

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“…In vivo evidence for the link between isoprenoid pyrophosphate deprivation and caspase-1 activation, which has been observed during drug-induced inhibition of mevalonate metabolism (36,47), was recently obtained in a genetic human disease, mevalonate kinase deficiency [MKD (49)]. In this rare hereditary, auto-inflammatory syndrome, the enzyme is inactive due to mutations of the encoding gene.…”

Section: Mevalonate Pathway Inhibitors Can Induce Innate Lymphocyte Amentioning

confidence: 99%

Novel Aspects of Mevalonate Pathway Inhibitors as Antitumor Agents

Thurnher

Nussbaumer²,

Gruenbacher³

2012

Clinical Cancer Research

199

160

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The mevalonate pathway for cholesterol biosynthesis and protein prenylation has been implicated in various aspects of tumor development and progression. Certain classes of drugs, such as statins and bisphosphonates, inhibit mevalonate metabolism and therefore have also been tested as antitumor agents. This concept is strongly supported by the recent finding that mutant p53, which is present in more than half of all human cancers, can significantly upregulate mevalonate metabolism and protein prenylation in carcinoma cells. The first evidence that mevalonate pathway inhibitors may have the potential to reverse the malignant phenotype has already been obtained. Moreover, recently discovered immunomodulatory properties of statins and bisphosphonates may also contribute to their known anticancer effects. Druginduced inhibition of protein prenylation may induce sequential cellular stress responses, including the unfolded protein response and autophagy, that eventually translate into inflammasome-dependent and caspase-1-mediated activation of innate immunity. This review focuses on these novel capabilities of mevalonate pathway inhibitors to beneficially affect tumor biology and contribute to tumor immune surveillance. Clin Cancer Res; 18(13); 3524-31. Ó2012 AACR.

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The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency

Cited by 49 publications

References 14 publications

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

DC-like cell-dependent activation of human natural killer cells by the bisphosphonate zoledronic acid is regulated by γδ T lymphocytes

Novel Aspects of Mevalonate Pathway Inhibitors as Antitumor Agents

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