title: LXRα represses LPS-induced inflammatory responses by competing with IRF3 for GRIP1 in Kupffer cells.
abstract: Liver X receptors (LXRs) in the nucleus play important roles in lipid metabolism and inflammation. The mechanism of LXR regulation of the LPS-induced Toll-like receptor 4 (TLR4) inflammatory signaling pathway remains to be elucidated. C57/BL6 mice were randomly divided into four groups: control, T0901317 (a LXRs agonist), LPS and T0901317+LPS. Additionally, Kupffer cells isolated from male C57/BL6 mice were divided into the same four groups. A decreased amount of inflammatory cells infiltrated the portal areas and the hepatic sinusoids in the livers of mice in the T0901317+LPS group than in those of mice in the LPS group. In the T0901317+LPS group, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor alpha (TNF-α) were lower, while the serum level of interleukin-10 (IL-10) was higher. In vitro, Kupffer cells pretreated with T0901317 for 24h presented reduced TNF-α, interferon-beta (IFN-β) and interleukin-1 beta (IL-1β) levels, while the IL-10 level increased; however, the mRNA and protein expression levels of interferon regulatory factor 3 (IRF3) and glucocorticoid receptor-interacting protein 1 (GRIP1) were not significantly reduced. The co-IP data illustrated that LXRα bound to GRIP1 specifically in the T0901317+LPS group, while less IRF3 was bound to GRIP1 in the T0901317+LPS group than in the LPS group. Furthermore, the DNA-binding activity of NF-κB was decreased by pretreating Kupffer cells with T0901317 for 24h. These results suggest that activated LXRα competes with IRF3 for GRIP1 binding, thus repressing IRF3 and NF-κB transcriptional activity and inhibiting the inflammatory response initiated by LPS in Kupffer cells.
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Chun-Mu
authors.initials: CM
authors.lastname: Miao
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Pei-Zhi
authors.initials: PZ
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Zuo-Jin
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Xi-Wen
authors.initials: XW
authors.lastname: Zhu
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Zhi-Bing
authors.initials: ZB
authors.lastname: Ou
authors.affiliation: Center for Lipid Research, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xiong-Zhong
authors.initials: XZ
authors.lastname: Ruan
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Gong
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China. Electronic address: liuchangan120@163.com.
authors.forename: Chang-An
authors.initials: CA
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D018836:Inflammation Mediators / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007728:Kupffer Cells / Q000187:drug effects* / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides / Q000276:immunology; D000071518:Liver X Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C491309:Grip1 protein, mouse; C494233:Irf3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C493487:Tlr4 protein, mouse
keywords: Glucocorticoid receptor-interacting protein 1; Interferon regulatory factor 3; Kupffer cell; Liver X receptor; Nuclear factor-kappa B