An evaluation of the anti-inflammatory properties of the pregnane X receptor gene isoforms PXR1 and PXR3

Abstract

The pregnane X receptor (PXR) is a nuclear receptor (NR) that primarily activates genes involved in drug metabolism. However, PXR also suppresses inflammation. This study investigated the anti-inflammatory activity of PXR1 and the minor isoform PXR3. Luciferase reporter experiments showed that like wtPXR1, PXR1 mutants and wtPXR3 that are transcriptionally inactive suppressed pro-inflammatory gene expression. This suggests that PXR uses distinct regions and by extension mechanisms to induce and repress gene induction. This study hypothesised that PXR represses inflammation via a mechanism called transrepression. One crucial feature of transrepression is conjugation with Small Ubiquitin-like Modifier (SUMO) proteins. Pull-down assays showed that both wtPXR1 and wtPXR3 are targets for conjugation with SUMO1, –2 and –3 proteins. The mutagenesis of putative SUMO conjugation sites revealed that residues K170 and K108 within PXR1 and PXR3, respectively, are important for their transrepressive activity. Collectively, these findings provide further insight into the anti-inflammatory properties of PXR.