A new mechanism of inhibition of IL-1β secretion by celastrol through the NLRP3 inflammasome pathway

Abstract

The NLRP3 (NOD-like receptor protein 3) inflammasome is a caspase-1-containing multiprotein complex that controls the release of IL-1β and has been associated with the development of inflammatory diseases. Celastrol, a pharmacologically active ingredient extracted from Tripterygium wilfordii Hook, has anti-inflammatory activities based on its inhibition of IL-1β secretion. The purpose of the present study was to investigate the possible modulation of NLRP3 inflammasome-mediated IL-1β and IL-18 release from macrophages by celastrol. It was shown that celastrol significantly reduced the secretion of IL-1β and IL-18 by inhibiting the expression of NLRP3 and the cleavage of caspase-1 in lipopolysaccharide (LPS)/ATP-induced macrophages. In addition, celastrol suppressed pyroptosis in macrophages, demonstrated by caspase-1 activation, LDH leakage and PI uptake assays. Furthermore, these inhibitory effects of celastrol were found to be at least partially achieved by decreasing the up-regulation of reactive oxygen species generation and NF-κB activation. Taken together, these findings suggested a new anti-inflammation mechanism of celastrol through inhibition of the NLRP3 inflammasome.