Long-term treatment of individuals with the macrolide antibiotic and prototypical activator

Long-term treatment of individuals with the macrolide antibiotic and prototypical activator of pregnane X receptor (PXR) rifampicin (Rif) inhibits the inflammatory response in liver. of the nuclear receptor (NR) protein pregnane X receptor (PXR; NR1I2) tends to suppress humoral and cellular immunological function in liver cells in patients (P?unescu 1970 This phenomenon has clinical significance especially in HIV-infected patients presenting with comorbid and highly drug-resistant strains of tuberculosis who are being treated Mouse monoclonal to MUSK with Rif where a compromised immune response is potentially lethal. Bardoxolone An improved understanding of the molecular basis of reduced immune function in Rif-treated patients could lead to the development of new therapeutic strategies to combat inflammatory liver diseases. Because PXR is Bardoxolone a molecular target of Rif we hypothesized that the PXR protein is targeted by the inflammatory signaling pathway in some manner so as to compromise the ability of Rif-treated hepatocytes to mount an immunological response to infection and inflammation. Several reports indicate that key members of the NR superfamily are SUMOylated to repress the inflammatory responses in various tissue types. It is noteworthy that Pascual et al. (2005) presented a model for repression in mouse macrophages in which ligand-dependent SUMOylation of peroxisome proliferator-activated receptor γ results in its recruitment to the promoters of several inflammatory-response genes where it inhibits transcription by preventing clearance of multiprotein corepressor complexes. Other evidence indicates that ligand-mediated SUMOylation of liver Bardoxolone organ X receptor NR protein plays a crucial function in transrepression of inflammatory response genes in cultured human brain astrocytes (Lee et al. 2009 PXR is certainly highly portrayed in liver organ and may be the molecular focus on of numerous medically prescribed drugs medication metabolites and substances in several trusted herbal treatments (Staudinger et al. 2001 Brobst et al. 2004 Staudinger and Ding 2005 Ding et al. 2006 Activation of hepatic PXR by these substances represents the molecular basis of the adaptive response that protects hepatocytes from poisonous insult and at the same time creates possibly life-threatening drug-drug herb-drug and food-drug connections in sufferers on mixture therapy. Although very much is known about the identification of ligands and focus on genes for PXR fairly little is well known about the molecular user interface of sign transduction pathways with this essential hepatic transcription aspect. The PXR proteins has recently been proven to be the mark Bardoxolone of many sign transduction cascades that modulate its phosphorylation position and transcriptional activity (Lichti-Kaiser et al. 2009 b; Pondugula Bardoxolone et al. 2009 A report indicates a substantial upsurge in liver-enriched transcription aspect cross-talk in sufferers with severe liver organ disease suggesting an elevation in the organize legislation of hepatic gene appearance occurs through the inflammatory response (Congiu et al. 2009 Two reviews have referred to mutually repressive and harmful cross-talk between your PXR and NF-κB signaling pathways (Gu et al. 2006 Zhou Bardoxolone et al. 2006 It as a result seems most likely that coordinate legislation of genes involved with both irritation and xenobiotic fat burning capacity occurs within a widespread response to the contamination and inflammatory responses although the molecular basis for these phenomena is not fully known. Species-specific effects are often observed when examining signal transduction pathways and activating ligands of PXR (Xie et al. 2000 Lichti-Kaiser et al. 2009 It is therefore important to examine PXR function in several cell models where possible. Here we use immortalized cell lines transgenic “humanized” PXR mice and primary cultures of mouse and human hepatocytes to show that SUMOylation of the PXR protein represents the molecular basis of the diminished inflammatory response observed across species. Our data support the idea that tumor necrosis factor α (TNFα) signaling in hepatocytes produces increased SUMOylation of the liganded PXR protein by incorporation of SUMO3 chains. We show here that this SUMOylated form of the PXR protein represses NF-κB target gene expression but has little effect on CYP3A gene expression in reporter gene assays. These data provide a plausible molecular explanation for how the PXR NR protein can be.