Abstract
Pregnane X receptor (PXR) is a nuclear receptor that plays a critical role in regulating the metabolism of xenobiotics. Here we report a new role for PXR as a negative regulator of the inflammatory pathway. Quiescent Pxr-/- BMDMs exhibited a pro-inflammatory state as transcripts of inflammatory genes were significantly elevated. Upon stimulation with Listeria monocytogenes (Lm), Pxr-/- BMDMs produced significantly higher protein levels of inflammatory cytokines. Moreover, enhanced inflammation was also observed in Pxr-/- mice challenged with Lm. Furthermore, disruption of the toll-like receptor 4 (TLR4) gene reversed the pro-inflammatory state in Pxr-/- BMDMs suggesting that PXR negatively regulated inflammation through the TLR4 pathway. In fact, both Pxr-/-Tlr4-/- BMDMs and mice exhibited normal inflammation in response to Lm infection. Transfection of HEK-Blue™-mTLR4 cells with DNA vector expressing PXR inhibited the response to LPS in a dose-dependent manner, which suggested that PXR can directly modulate the TLR4 pathway. In conclusion, our study demonstrates that PXR negatively regulates the inflammatory pathway and the regulation is through directly modulating the TLR4 pathway. Thus, our results suggest that PXR can be targeted as a therapeutic strategy to treat inflammatory diseases.
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