| First Author | Okamura M | Year | 2020 |
| Journal | Cells | Volume | 9 |
| Issue | 10 | PubMed ID | 33076328 |
| Mgi Jnum | J:309268 | Mgi Id | MGI:6705485 |
| Doi | 10.3390/cells9102296 | Citation | Okamura M, et al. (2020) PXR Functionally Interacts with NF-kappaB and AP-1 to Downregulate the Inflammation-Induced Expression of Chemokine CXCL2 in Mice. Cells 9(10):2296 |
| abstractText | Pregnane X receptor (PXR) is a liver-enriched xenobiotic-responsive transcription factor. Although recent studies suggest that PXR shows anti-inflammatory effects by suppressing nuclear factor kappa B (NF-kappaB), the detailed mechanism remains unclear. In this study, we aimed to elucidate this mechanism. Mice were treated intraperitoneally with the PXR agonist pregnenolone 16alpha-carbonitrile (PCN) and/or carbon tetrachloride (CCl4). Liver injury was evaluated, and hepatic mRNA levels were determined via quantitative reverse transcription polymerase chain reaction. Reporter assays with wild-type and mutated mouse Cxcl2 promoter-containing reporter plasmids were conducted in 293T cells. Results showed that the hepatic expression of inflammation-related genes was upregulated in CCl4-treated mice, and PCN treatment repressed the induced expression of chemokine-encoding Ccl2 and Cxcl2 among the genes investigated. Consistently, PCN treatment suppressed the increased plasma transaminase activity and neutrophil infiltration in the liver. In reporter assays, tumor necrosis factor-alpha-induced Cxcl2 expression was suppressed by PXR. Although an NF-kappaB inhibitor or the mutation of an NF-kappaB-binding motif partly reduced PXR-dependent suppression, the mutation of both NF-kappaB and activator protein 1 (AP-1) sites abolished it. Consistently, AP-1-dependent gene transcription was suppressed by PXR with a construct containing AP-1 binding motifs. In conclusion, the present results suggest that PXR exerts anti-inflammatory effects by suppressing both NF-kappaB- and AP-1-dependent chemokine expression in mouse liver. |
