Open AccessActivation of liver X receptor attenuates lysophosphatidylcholine‐induced IL ‐8 expression in endothelial cells via the NF ‐κB pathway and SUMO ylation
Author(s) -
Bi Xukun,
Song Jiale,
Gao Jing,
Zhao Juanjuan,
Wang Meihui,
Scipione Corey A.,
Koschinsky Marlys L.,
Wang Zhao V.,
Xu Shiming,
Fu Guosheng
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12903
Subject(s) - sumo protein , liver x receptor , agonist , transrepression , gene knockdown , chemistry , iκbα , microbiology and biotechnology , proinflammatory cytokine , signal transduction , biology , receptor , nf κb , nuclear receptor , inflammation , transcription factor , biochemistry , ubiquitin , immunology , transactivation , apoptosis , gene
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 GW 3965 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 ( HUVEC s). 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 HUVEC s. 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 SUMO ylation or the treatment of LXR agonist. After enhancing SUMO ylation by knockdown SUMO ‐specific protease Sentrin‐specific protease 1 (SENP1), the inhibition of GW 3965 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 SUMO ylation. Our results suggest that LXR agonist exerts the anti‐atherosclerotic role by attenuation of the NF ‐κB pathway in endothelial cells.