The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock

Lugrin, Jérôme; Ciarlo, Eleonora; Santos, Alba; Grandmaison, Gaël; Santos, Isis Dos; Roy, Didier Le; Roger, Thierry

doi:10.1016/j.bbamcr.2013.03.004

Cited by 56 publications

(39 citation statements)

References 81 publications

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“…Use of three structurally unrelated sirtuin inhibitors, including compound 64, 35 the most potent and specific SIRT2 inhibitor described to date, and cambinol, a previously described putative pan-sirtuin inhibitor, 47,48 largely confirmed our working hypothesis, as incubation of cells in the presence of these compounds Figure 4 Cambinol interferes with the molecular execution of necroptosis. (a) Cambinol (100 μM) or necrostatin-1 (20 μM)-treated L929 cells were incubated in the presence of hTNF (1 ng/ml) for 20 min and the phosphorylated status of JNK determined by western blot (n = 3).…”

Section: Discussionmentioning

confidence: 55%

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

et al. 2015

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Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD + ) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD + promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD + -dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD + does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors. + as a substrate in a number of regulatory processes has shed a new light on its role in cell physiology. Indeed, NAD + represents a substrate for a wide range of enzymes including cADP-ribose synthases, poly (ADP-ribose) polymerases (PARPs) and the sirtuin family of NAD + -dependent deacylases (SIRTs). In marked contrast to its role in energy metabolism, the involvement of NAD + in these enzymatic reactions is based on its ability to function as a donor of ADP-ribose, a reaction that, if sustained, can lead to the depletion of the intracellular NAD + pool. 1-5The pro-survival role of NAD + has been particularly well described in cells exposed to genotoxic/oxidative stress. In response to DNA damage, PARP1, the founding and most abundant member of the PARP family, binds to DNA strand breaks and initiates a repair response by catalyzing the posttranslational modification of several nuclear proteins, including itself. This protective response is characterized by the transfer of successive units of the ADP-ribose moiety (up to 200 units) from NAD + to other proteins, compromising therefore both energy production (slowing the rate of glycolysis, electron transport and ATP formation) and activity of other NAD + -dependent enzymes through NAD + depletion. 6,7 Moreover, PARP1-synthesized PAR polymers can be degraded into free oligomers, known to translocate to the mitochondria where they can trigger the release of AIF from mitochondria to the nucleus. [8][9][10][11] The precise molecular steps linking PARP1 activation to this form of stress-induced cell death, termed parthanatos, have not been fully elucidated, and...

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Section: Discussionmentioning

confidence: 55%

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

et al. 2015

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“…Mice which received Tubustatin during a hemorrhagic shock model were subsequently protected from sepsis following cecal ligation and puncture in a two hit model of sepsis (Cheng et al, 2015). Furthermore, mice treated with the SIRT1 and 2 inhibitor, Cambinol, were protected from endotoxic and toxic shock (Lugrin et al, 2013). …”

Section: Epigenetics and Non-viral Infectionsmentioning

confidence: 99%

The therapeutic potential of epigenetic manipulation during infectious diseases

Morris

Dickman

Dockrell

2016

Pharmacology & Therapeutics

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Epigenetic modifications are increasingly recognized as playing an important role in the pathogenesis of infectious diseases. They represent a critical mechanism regulating transcriptional profiles in the immune system that contributes to the cell-type and stimulus specificity of the transcriptional response. Recent data highlight how epigenetic changes impact macrophage functional responses and polarization, influencing the innate immune system through macrophage tolerance and training. In this review we will explore how post-translational modifications of histone tails influence immune function to specific infectious diseases. We will describe how these may influence outcome, highlighting examples derived from responses to acute bacterial pathogens, models of sepsis, maintenance of viral latency and HIV infection. We will discuss how emerging classes of pharmacological agents, developed for use in oncology and other settings, have been applied to models of infectious diseases and their potential to modulate key aspects of the immune response to bacterial infection and HIV therapy.

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“…It has also been documented that the inhibition of SIRT1 and SIRT2 decreases the toll-like receptor (TLR)-induced activation of macrophages and the production of pro-inflammatory cytokines and other mediators by blocking the activation of mitogen-activated protein kinase (MAPK) and MAPK/extracellular signal-regulated kinase (9). In summary, accumulated data (8,9) indicate that SIRTs can affect both the innate and adaptive immune responses.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, SIRT6 protein levels are reported to be moderately increased in the same arthritis experimental model (12). The effect of SIRTs on epigenetics, intracellular pathways, and cytokines suggests that they play a role in the pathogenesis of RA (8,9). This study aimed to evaluate SIRT2 and SIRT3 mRNA expressions in patients with RA and to determine their potential effects on the disease phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Changes in sirtuin 2 and sirtuin 3 mRNA expressions in rheumatoid arthritis

Kara¹,

Yolbaş²,

Şahin³

et al. 2017

Eur J Rheumatol

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Objective: Sirtuins (SIRTs) play a prominent role in metabolism, apoptosis, aging, inflammation, and epigenetics. Inflammation, apoptosis, and epigenetics are pathogenic issues in rheumatoid arthritis (RA). This study aimed to evaluate SIRT2 and SIRT3 mRNA expressions in patients with RA.Material and Methods: Fifty-four patients with RA and 26 healthy controls were enrolled. Disease activity was determined using the disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (score of >2.6 was considered to be active). SIRT2 and SIRT3 mRNA expressions in the extracellular plasma were investigated by real-time PCR.Results: SIRT3 mRNA expression was higher in the RA group than in the healthy control group (4.64 fold, p<0.001), whereas SIRT2 mRNA expression was relatively lower in the RA group than in the healthy control group (0.55 fold, p=0.109). However, SIRT2 (1.73 fold, p=0.065) and SIRT3 (3.58 fold, p=0.051) mRNA expressions were relatively higher in patients with active RA than in those with inactive RA. Conclusion:In RA, SIRT3 mRNA expression is increased, whereas SIRT2 mRNA expression is decreased. Conversely, SIRT2 and SIRT3 mRNA expressions increase in active RA. Therefore, the fate of each SIRT may differ in RA.

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The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock

Cited by 56 publications

References 81 publications

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

The therapeutic potential of epigenetic manipulation during infectious diseases

Changes in sirtuin 2 and sirtuin 3 mRNA expressions in rheumatoid arthritis

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