title: Liver X receptor regulates mouse GM-CSF-derived dendritic cell differentiation in vitro.
abstract: Liver X receptors (LXRs) are nuclear receptors that play an essential role in lipid and cholesterol metabolism. Emerging studies indicate a potential function for LXRs in regulating dendritic cell (DC)-dependent immune responses; however, the role of LXRs in DC differentiation is largely unknown. Here, we report that LXRα regulates the differentiation of mouse GM-CSF-derived DCs. Activation or overexpression of LXRα significantly enhanced myeloid DC differentiation from mouse bone marrow (BM) cells, while siRNA-mediated knockdown of LXRα suppressed DC differentiation. In addition, we demonstrated that LXR agonist-programmed DCs showed an increased capacity for stimulating T-cell proliferation. Mechanistic studies showed that activation of LXR could inhibit the phosphorylation of STAT3 and downregulate the expression of its target, S100A9, an important negative regulator of myeloid DC differentiation. We also found that Histone deacetylase (HDAC) inhibition interfered with the effect of LXR on STAT3 signaling via acetylation of STAT3. Chromatin immunoprecipitation assays confirmed that LXR activation and HDAC inhibition balanced the recruitment of STAT3 to the S100A9 promoter, which involved distinct post-translational modifications of STAT3. In conclusion, our observations demonstrated a novel role for LXRα in GM-CSF-derived DC differentiation and revealed the underlying mechanism.
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Chinese Ministry of Education, Guangzhou, China. Electronic address: zhouj72@mail.sysu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D040502:Calgranulin B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D040502:Calgranulin B; D056572:Histone Deacetylase Inhibitors; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; C576329:S100A9 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006655:Histone Deacetylases
keywords: Dendritic cell; JAK/STAT3 pathway; Liver X receptor