The antibiotic rifampicin (Rif), an activator of the nuclear receptor pregnane X receptor (PXR; NR1l2) suppresses humoral and cellular inmmunological functions in liver cells. Hu et al. wanted to understand the molecular basis of reduced immune function in Rif-treated patients because this could lead to new therapeutic strategies for combating inflammatory liver diseases. Using immortalized human cell lines, transgenic “humanized” PXR mice, and primary cultures of mouse and human hepatocytes, they demonstrated that compounds such as Rif induce the SUMOylation of the liganded PXR protein. This SUMOylation produces a form of the PXR protein that represses nuclear factor κB (NFκB) target gene expression, thus explaining the negative regulation of the inflammatory response in hepatocytes after Rif treatment. Like peroxisome proliferator-activated receptor-mediated repression of NFκB, these data suggest the possibility that the molecular mechanism of repression could involve selective targeting of the PXR to the nuclear receptor corepressor/histone deacetylase 3 repressor complexes on inflammatory gene promoters. These data form the basis of a new molecular paradigm seeking to exploit the interactions between ligand-mediated PXR activation, SUMOylation of PXR, and inflammatory liver and bowel diseases.
See article at J Pharmacol Exp Ther 2010, 335:342–350.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics