Anti-inflammatory Compounds Parthenolide and Bay 11-7082 Are Direct Inhibitors of the Inflammasome

Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2010; 285(13):9792-802. DOI: 10.1074/jbc.M109.082305
Source: PubMed


Activation of the inflammasome generates the pro-inflammatory cytokines interleukin-1 beta and -18, which are important mediators of inflammation. Abnormal activation of the inflammasome leads to many inflammatory diseases, including gout, silicosis, neurodegeneration, and genetically inherited periodic fever syndromes. Therefore, identification of small molecule inhibitors that target the inflammasome is an important step toward developing effective therapeutics for the treatment of inflammation. Here, we show that the herbal NF-kappaB inhibitory compound parthenolide inhibits the activity of multiple inflammasomes in macrophages by directly inhibiting the protease activity of caspase-1. Additional investigations of other NF-kappaB inhibitors revealed that the synthetic I kappaB kinase-beta inhibitor Bay 11-7082 and structurally related vinyl sulfone compounds selectively inhibit NLRP3 inflammasome activity in macrophages independent of their inhibitory effect on NF-kappaB activity. In vitro assays of the effect of parthenolide and Bay 11-7082 on the ATPase activity of NLRP3 demonstrated that both compounds inhibit the ATPase activity of NLRP3, suggesting that the inhibitory effect of these compounds on inflammasome activity could be mediated in part through their effect on the ATPase activity of NLRP3. Our results thus elucidate the molecular mechanism for the therapeutic anti-inflammatory activity of parthenolide and identify vinyl sulfones as a new class of potential therapeutics that target the NLRP3 inflammasome.

Download full-text


Available from: Christine Juliana, Aug 19, 2015
  • Source
    • "As pyroptosis is thought to contribute to the pathogenesis of a broad spectrum of disease, characterized by excessive/uncontrolled cell death and inflammation, compounds endowed with anti-pyroptotic activity are of interest due to their therapeutic potential [8]. A group of structurally unrelated small molecules, including parthenolide and Bay 11-7082 [9], resatorvid/TAK-242, 5Z-7-oxozeaneol, and bromoxone [10], compound 9 and related derivatives [11] (Figure S1A) have been shown to prevent pyroptosis in in vitro experiments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fumaric acid esters (FAEs) exert therapeutic effects in patients with psoriasis and multiple sclerosis, however their mode of action remains elusive. Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death, mediated by the activation of inflammasomes. To understand the pharmacological basis of the therapeutic effects of FAEs, the anti-pyroptotic activity of dimethyl fumarate (DMF) and its hydrolysis metabolite monomethyl fumarate (MMF) was studied in a model of NLRP3 inflammasome-mediated pyroptosis of human macrophages. Phorbol myristate acetate-differentiated THP-1 cells were exposed to lipopolysaccharide (5 μg/ml; 4 h), then pulsed with ATP (5 mM; 1 h). MMF, DMF, or parthenolide (positive control) were added 1 h before the ATP pulse. The pyroptotic cell death was evaluated by morphological examination and quantified by measuring the lactate dehydrogenase leakage. The ATP-triggered death of THP-1 cells (60.4 ± 4.0%) was significantly (P < 0.01) prevented by DMF, in a time- and concentration-dependent manner (pIC50 and maximal effect were 6.6 and 67.6±1.2%, respectively). MMF was less efficacious than DMF. These effects were accompanied by a decreased intracellular activation of caspase-1 and interleukin-1β release from ATP-treated cells, thus suggesting that FAEs antagonise the effects of ATP by preventing the activation of the pyroptotic molecular cascade leading to cell death. These results indicate that FAEs are endowed with anti-pyroptotic activity, which may contribute to their therapeutic effects.
    Full-text · Article · Sep 2015 · International Immunopharmacology
  • Source
    • "Consistent with the idea that PN inhibits progression of the inflammatory response, it reduces cardiovascular damage in endotoxic shock, retards atherosclerotic lesions, and has beneficial effects in myocardial ischemia in vivo [18, 33, 34]. It has been shown that PN is a direct inhibitor of the protease activity of caspase-1 by alkylating critical cysteine residues in the p20 subunit [35]. In addition, it is a good inhibitor of the Nlrp3 inflammasome and that this activity is independent of the inhibitory effect of PN on the NF-κB pathway. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Parthenolide (PN) has been proved to elicit a wide range of biological activities through its anti-inflammatory action in the treatment of migraine, arthritis, and atherosclerosis. To decide whether this effect applies to ischemic injury in brain, we therefore investigate the potential neuroprotective role of PN and the underlying mechanisms. Male Sprague-Dawley rats were randomly divided into Saline, Vehicle, and PN groups and a permanent middle cerebral artery occlusion (MCAO) model was used. PN administered intraperitoneally immediately after cerebral ischemia and once daily on the following days. At time points after MCAO, neurological deficit, infarct volume, and brain water content were measured. Immunohistochemistry, western blot and RT-PCR were used to analyze the expression of NF- κ B and caspase-1 in ischemic brain tissue. Phospho-p38MAPK and claudin-5 were detected by western blot. The results indicated that PN dramatically ameliorated neurological deficit, brain water content, and infarct volume, downregulated NF- κ B, phospho-p38MAPK, and caspase-1 expressions, and upregulated claudin-5 expression in ischemic brain tissue. Conclusions: PN protected the brain from damage caused by MCAO; this effect may be through downregulating NF- κ B, phosho-p38MAPK, and caspase-1 expressions and ameliorating BBB permeability.
    Full-text · Article · Jul 2013 · Mediators of Inflammation
  • Source
    • "Consistent with the findings reported in the present study, BAY 11-7082 and BAY 11-7085 have been reported to inhibit the NALP3 inflammasome in macrophages by an NF-κB-independent mechanism [43]. The NALP3 inflammasome processes pro-IL-1β and pro-IL-18 into the active pro-inflammatory cytokines IL-1β and IL-18 respectively. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The compound BAY 11-7082 inhibits IκBα phosphorylation in cells and has been used to implicate the canonical IκB kinases (IKKs) and NFκB in <350 publications. Here we report that BAY 11-7082 does not inhibit the IKKs but suppresses their activation in LPS-stimulated RAW macrophages and IL-1-stimulated IL-1R HEK293 cells. BAY 11-7082 exerts these effects by inactivating the E2 conjugating enzymes Ubc13 and UbcH7 and the E3 ligase LUBAC (linear ubiquitin assembly complex), thereby preventing the formation of Lys63-linked and linear-polyubiquitin chains. BAY 11-7082 prevents ubiquitin conjugation to Ubc13 and UbcH7 by forming a covalent adduct with their reactive cysteine residues via Michael addition at the C3 atom of BAY 11-7082, followed by the release of 4-methylbenzene-sulphinic acid. BAY 11-7082 stimulated Lys48-linked polyubiquitin chain formation in cells and protected HIF1a (hypoxia-inducible factor 1a) from proteasomal degradation, suggesting that it inhibits the proteasome. Our results indicate that the anti-inflammatory effects of BAY 11-7082, its ability to induce B cell lymphoma and leukaemic T cell death and to prevent the recruitment of proteins to sites of DNA damage are exerted via inhibition of components the ubiquitin system and not by inhibiting NFκB.
    Full-text · Article · Feb 2013 · Biochemical Journal
Show more