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.

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Available from: Christine Juliana, Aug 19, 2015
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    • "The adduction of DMF and MMF to the free thiol group of glutathione (GSH) [12] and in the side chain of certain cysteine residues in proteins [13] has been demonstrated, and it has been shown that DMF is more reactive than MMF toward these functional groups. Interestingly, albeit structurally unrelated, most of the anti-pyroptotic compounds so far identified have electrophilic substructures (Fig. S1A), and Michael-like reactions with free thiol groups in proteins of the pyroptotic cascades have been postulated to underlie their activity [9] [10] [11]. FAEs even are Michael acceptors (Fig. S1B), and the adduction to biological targets (i.e., GSH, Keap-1) has been already suggested to mediate their effects [14] [15] [16]. "
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    • "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. "
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    • "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. "
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