Inflammation is a common pathophysiological process as well as a clinical threat that occurs in various diseases worldwide. It is well-documented that nuclear factor-κB (NF-κB) and mitogen-activated protein kinase pathways are involved in inflammatory reactions to microbial infections in lipopolysaccharide (LPS)-activated macrophages. The deubiquitinase ubiquitin carboxyl-terminal hydrolase-L1 (UCHL1) has been reported as an oncoprotein to promote the growth and progression of cancer cells. However, the regulatory mechanism of UCHL1 in inflammation is currently unclear. Here, we aimed to assess the effects of UCHL1 on LPS-associated inflammatory response in vitro and in vivo by enzyme-linked immunosorbent assay, quantitative reverse-transcription polymerase chain reaction, and western blot analysis. This study identified that inhibition or knockdown of UCHL1 decreased the amounts of the key pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α in macrophages. Additionally, inhibition of UCHL1 suppressed LPS-induced extracellular signal-regulated protein kinase 1/2 phosphorylation and NF-κB translocation by regulating the inhibitor of NF-κB. Mechanically, UCHL1 interacts with IκBα protein in THP-1. Meanwhile, inhibition of UCHL1 blocked the LPS-induced degradation of IκBα through the ubiquitin-proteasome system. Moreover, in vivo assay showed that suppression of UCHL1 notably reduced the LPS-induced animal death and release of pro-inflammatory cytokines. Overall, the current findings uncover that UCHL1 functions as a crucial regulator for inflammatory response via reversing the degradation of IκBα, representing a potential target for the treatment of inflammatory diseases.
Keywords: inflammation; macrophages; protein degradation; ubiquitin.
© 2021 International Federation for Cell Biology.