Activation of liver X receptor attenuates lysophosphatidylcholine-induced IL-8 expression in endothelial cells via the NF-κB pathway and SUMOylation

Xukun Bi, Jiale Song, Jing Gao, Juanjuan Zhao, Meihui Wang, Corey A. Scipione, Marlys L. Koschinsky, Zhao V. Wang, Shiming Xu, Guosheng Fu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The liver X receptor (LXR) is a cholesterol-sensing nuclear receptor that has an established function in lipid metabolism; however, its role in inflammation is elusive. In this study, we showed that the LXR agonist GW3965 exhibited potent anti-inflammatory activity by suppressing the firm adhesion of monocytes to endothelial cells. To further address the mechanisms underlying the inhibition of inflammatory cell infiltration, we evaluated the effects of LXR agonist on interleukin-8 (IL-8) secretion and nuclear factor-kappa B (NF-κB) activation in human umbilical vein endothelial cells (HUVECs). The LXR agonist significantly inhibited lysophosphatidylcholine (LPC)-induced IL-8 production in a dose-dependent manner without appreciable cytotoxicity. Western blotting and the NF-κB transcription activity assay showed that the LXR agonist inhibited p65 binding to the IL-8 promoter in LPC-stimulated HUVECs. Interestingly, knockdown of the indispensable small ubiquitin-like modifier (SUMO) ligases Ubc9 and Histone deacetylase 4 (HDAC4) reversed the increase in IL-8 induced by LPC. Furthermore, the LPC-induced degradation of inhibitory κBα was delayed under the conditions of deficient SUMOylation or the treatment of LXR agonist. After enhancing SUMOylation by knockdown SUMO-specific protease Sentrin-specific protease 1 (SENP1), the inhibition of GW3965 was rescued on LPC-mediated IL-8 expression. These findings indicate that LXR-mediated inflammatory gene repression correlates to the suppression of NF-κB pathway and SUMOylation. Our results suggest that LXR agonist exerts the anti-atherosclerotic role by attenuation of the NF-κB pathway in endothelial cells.

Original languageEnglish (US)
JournalJournal of Cellular and Molecular Medicine
DOIs
StateAccepted/In press - 2016

Fingerprint

Sumoylation
Lysophosphatidylcholines
NF-kappa B
Interleukin-8
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Ubiquitin
SUMO-1 Protein
Peptide Hydrolases
Histone Deacetylases
Liver X Receptors
Ligases
Cytoplasmic and Nuclear Receptors
Lipid Metabolism
Monocytes
Anti-Inflammatory Agents
Western Blotting
Cholesterol
Inflammation

Keywords

  • Liver X receptor
  • Lysophosphatidylcholine
  • NF-κB
  • SUMOylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Cite this

Activation of liver X receptor attenuates lysophosphatidylcholine-induced IL-8 expression in endothelial cells via the NF-κB pathway and SUMOylation. / Bi, Xukun; Song, Jiale; Gao, Jing; Zhao, Juanjuan; Wang, Meihui; Scipione, Corey A.; Koschinsky, Marlys L.; Wang, Zhao V.; Xu, Shiming; Fu, Guosheng.

In: Journal of Cellular and Molecular Medicine, 2016.

Research output: Contribution to journalArticle

Bi, Xukun ; Song, Jiale ; Gao, Jing ; Zhao, Juanjuan ; Wang, Meihui ; Scipione, Corey A. ; Koschinsky, Marlys L. ; Wang, Zhao V. ; Xu, Shiming ; Fu, Guosheng. / Activation of liver X receptor attenuates lysophosphatidylcholine-induced IL-8 expression in endothelial cells via the NF-κB pathway and SUMOylation. In: Journal of Cellular and Molecular Medicine. 2016.
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keywords = "Liver X receptor, Lysophosphatidylcholine, NF-κB, SUMOylation",
author = "Xukun Bi and Jiale Song and Jing Gao and Juanjuan Zhao and Meihui Wang and Scipione, {Corey A.} and Koschinsky, {Marlys L.} and Wang, {Zhao V.} and Shiming Xu and Guosheng Fu",
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T1 - Activation of liver X receptor attenuates lysophosphatidylcholine-induced IL-8 expression in endothelial cells via the NF-κB pathway and SUMOylation

AU - Bi, Xukun

AU - Song, Jiale

AU - Gao, Jing

AU - Zhao, Juanjuan

AU - Wang, Meihui

AU - Scipione, Corey A.

AU - Koschinsky, Marlys L.

AU - Wang, Zhao V.

AU - Xu, Shiming

AU - Fu, Guosheng

PY - 2016

Y1 - 2016

N2 - The liver X receptor (LXR) is a cholesterol-sensing nuclear receptor that has an established function in lipid metabolism; however, its role in inflammation is elusive. In this study, we showed that the LXR agonist GW3965 exhibited potent anti-inflammatory activity by suppressing the firm adhesion of monocytes to endothelial cells. To further address the mechanisms underlying the inhibition of inflammatory cell infiltration, we evaluated the effects of LXR agonist on interleukin-8 (IL-8) secretion and nuclear factor-kappa B (NF-κB) activation in human umbilical vein endothelial cells (HUVECs). The LXR agonist significantly inhibited lysophosphatidylcholine (LPC)-induced IL-8 production in a dose-dependent manner without appreciable cytotoxicity. Western blotting and the NF-κB transcription activity assay showed that the LXR agonist inhibited p65 binding to the IL-8 promoter in LPC-stimulated HUVECs. Interestingly, knockdown of the indispensable small ubiquitin-like modifier (SUMO) ligases Ubc9 and Histone deacetylase 4 (HDAC4) reversed the increase in IL-8 induced by LPC. Furthermore, the LPC-induced degradation of inhibitory κBα was delayed under the conditions of deficient SUMOylation or the treatment of LXR agonist. After enhancing SUMOylation by knockdown SUMO-specific protease Sentrin-specific protease 1 (SENP1), the inhibition of GW3965 was rescued on LPC-mediated IL-8 expression. These findings indicate that LXR-mediated inflammatory gene repression correlates to the suppression of NF-κB pathway and SUMOylation. Our results suggest that LXR agonist exerts the anti-atherosclerotic role by attenuation of the NF-κB pathway in endothelial cells.

AB - The liver X receptor (LXR) is a cholesterol-sensing nuclear receptor that has an established function in lipid metabolism; however, its role in inflammation is elusive. In this study, we showed that the LXR agonist GW3965 exhibited potent anti-inflammatory activity by suppressing the firm adhesion of monocytes to endothelial cells. To further address the mechanisms underlying the inhibition of inflammatory cell infiltration, we evaluated the effects of LXR agonist on interleukin-8 (IL-8) secretion and nuclear factor-kappa B (NF-κB) activation in human umbilical vein endothelial cells (HUVECs). The LXR agonist significantly inhibited lysophosphatidylcholine (LPC)-induced IL-8 production in a dose-dependent manner without appreciable cytotoxicity. Western blotting and the NF-κB transcription activity assay showed that the LXR agonist inhibited p65 binding to the IL-8 promoter in LPC-stimulated HUVECs. Interestingly, knockdown of the indispensable small ubiquitin-like modifier (SUMO) ligases Ubc9 and Histone deacetylase 4 (HDAC4) reversed the increase in IL-8 induced by LPC. Furthermore, the LPC-induced degradation of inhibitory κBα was delayed under the conditions of deficient SUMOylation or the treatment of LXR agonist. After enhancing SUMOylation by knockdown SUMO-specific protease Sentrin-specific protease 1 (SENP1), the inhibition of GW3965 was rescued on LPC-mediated IL-8 expression. These findings indicate that LXR-mediated inflammatory gene repression correlates to the suppression of NF-κB pathway and SUMOylation. Our results suggest that LXR agonist exerts the anti-atherosclerotic role by attenuation of the NF-κB pathway in endothelial cells.

KW - Liver X receptor

KW - Lysophosphatidylcholine

KW - NF-κB

KW - SUMOylation

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