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

Abstract

Activation of the inflammasome generates the pro-inflammatory cytokines interleukin-1␤ 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-B 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-B inhibitors revealed that the synthetic IB kinase-␤ inhibitor Bay 11-7082 and structurally related vinyl sulfone compounds selectively inhibit NLRP3 inflammasome activity in macrophages independent of their inhibitory effect on NF-B 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.

3,4-Methylenedioxy-β-nitrostyrene Inhibits NLRP3 Inflammasome Activation by Blocking Assembly of the Inflammasome

“…We used ELISA to measure the level of IL-1␤ in the culture supernatant as a readout for NLRP3 inflammasome activation. The compound Bay 11-7082 inhibited Nlrp3 inflammasome activation in accordance with a previous report (22). We identified an additional chemical compound, MNS, that consistently abolished IL-1␤ secretion in our screening experiments (Fig.…”

“…6H). Bay 11-7082 has been reported to inhibit the ATPase activity of NLRP3 possibly through the mechanism of cysteine modification (22). We (Fig.…”

The Lysosome Rupture-activated TAK1-JNK Pathway Regulates NLRP3 Inflammasome Activation

“…It has been reported that TAK1 is involved in NLRP3 inflammasome activation in an NF-B activity-dependent manner to facilitate classical NLRP3 agonist stimulation (23) or hypotonic stress-induced cell volume change (24). However, although Bay11-7082 is an inhibitor of the NF-B pathway, this compound has recently been proposed as a direct NLRP3 inhibitor independent of the NF-B pathway (25). Therefore, how TAK1 is involved in NLRP3 inflammasome activation remains unclear.…”

A lipid nanoparticle for the efficient delivery of siRNA to dendritic cells

“…Thus, the presence of cathepsin B in the cytosol is an indicator of the extent of disruption of endosomes [29,30]. To examine the amount of cathepsin B released from endosomes to the cytosol, the plasma membrane was made permeable by a digitonin treatment.…”