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Pregnane X receptor negatively regulates inflammation by directly modulating the Toll-like receptor 4 pathway (IRM5P.701)

Zhijuan Qiu, Basak Cicek, Jorge Cervantes, Juan Salazar, Sridhar Mani and Kamal Khanna
J Immunol May 1, 2014, 192 (1 Supplement) 62.2;
Zhijuan Qiu
1Immunology, University of Connecticut Health Center, Farmington, CT
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Basak Cicek
1Immunology, University of Connecticut Health Center, Farmington, CT
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Jorge Cervantes
2Pediatrics, University of Connecticut Health Center, Farmington, CT
1Immunology, University of Connecticut Health Center, Farmington, CT
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Juan Salazar
2Pediatrics, University of Connecticut Health Center, Farmington, CT
1Immunology, University of Connecticut Health Center, Farmington, CT
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Sridhar Mani
3Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY
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Kamal Khanna
1Immunology, University of Connecticut Health Center, Farmington, CT
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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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The Journal of Immunology
Vol. 192, Issue 1 Supplement
1 May 2014
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Pregnane X receptor negatively regulates inflammation by directly modulating the Toll-like receptor 4 pathway (IRM5P.701)
Zhijuan Qiu, Basak Cicek, Jorge Cervantes, Juan Salazar, Sridhar Mani, Kamal Khanna
The Journal of Immunology May 1, 2014, 192 (1 Supplement) 62.2;

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Pregnane X receptor negatively regulates inflammation by directly modulating the Toll-like receptor 4 pathway (IRM5P.701)
Zhijuan Qiu, Basak Cicek, Jorge Cervantes, Juan Salazar, Sridhar Mani, Kamal Khanna
The Journal of Immunology May 1, 2014, 192 (1 Supplement) 62.2;
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Print ISSN 0022-1767        Online ISSN 1550-6606