title: Activation of liver X receptor attenuates lysophosphatidylcholine-induced IL-8 expression in endothelial cells via the NF-κB pathway and SUMOylation.
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.
authors.affiliation: Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Xukun
authors.initials: X
authors.lastname: Bi
authors.affiliation: Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Jiale
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Meihui
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Scipione
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada.
authors.forename: Marlys L
authors.initials: ML
authors.lastname: Koschinsky
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.|Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Shiming
authors.initials: S
authors.lastname: Xu
authors.affiliation: Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Fu
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism*; D000071518:Liver X Receptors / Q000819:agonists / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D058207:Sumoylation / Q000187:drug effects*
chemical_list: D016209:Interleukin-8; D000071518:Liver X Receptors; D008244:Lysophosphatidylcholines; D016328:NF-kappa B
keywords: NF-κB; SUMOylation; liver X receptor; lysophosphatidylcholine