Inhibition of immunoproteasome attenuates NLRP3 inflammasome formation in tumor necrosis factor α-stimulated intestinal epithelial cell
Article
Yoon, B, Yun, Y, Kim, KB et al. (2022). Inhibition of immunoproteasome attenuates NLRP3 inflammasome formation in tumor necrosis factor α-stimulated intestinal epithelial cell
. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 624 157-163. 10.1016/j.bbrc.2022.07.120
Yoon, B, Yun, Y, Kim, KB et al. (2022). Inhibition of immunoproteasome attenuates NLRP3 inflammasome formation in tumor necrosis factor α-stimulated intestinal epithelial cell
. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 624 157-163. 10.1016/j.bbrc.2022.07.120
Excessive release of inflammatory cytokines has been considered as a major cause of chronic inflammation, resulting in intestinal barrier disruption that leads to inflammatory bowel disease (IBD). Tumor necrosis factor α (TNFα) is one of the well-known inflammatory cytokines that activates formation of NLRP3 inflammasome, thus resulting in excessive secretion of inflammatory cytokines causing IBD. Although immunoproteasome inhibitors have been reported to inhibit inflammatory cytokine release, immunoproteasome inhibition has not yet been addressed for attenuation of NLRP3 inflammasome activity in intestinal epithelial cell. Here, we observed that NLRP3 inflammasome assembly was attenuated by peptide epoxyketone YU102, a LMP2 subunit immunoproteasome inhibitor, in intestinal epithelial cell. YU102 also inhibited maturation of active caspase-1 and secretion of IL-1β, which are subsequent inflammatory cascade after the formation of NLRP3 inflammasome. Progression of epithelial-mesenchymal transition and increase of cellular permeability, which were induced by TNFα, were also suppressed through inhibition of immunoproteasome. Furthermore, we found that YU102 does not inhibit degradation of IкBα and its following NF-кB activation that leads to transcription of NLRP3. These findings suggest that inhibition of immunoproteasome with YU102 offers a potential therapeutic premise for prevention of TNFα-induced chronic inflammation through attenuation of NLRP3 inflammasome assembly.
