title: Telomerase reverse transcriptase acts in a feedback loop with NF-κB pathway to regulate macrophage polarization in alcoholic liver disease.
abstract: Activation of Kupffer cells (KCs) plays a central role in the pathogenesis of alcoholic liver disease (ALD). C57BL/6 mice fed EtOH-containing diet showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Since telomerase activation occurs at critical stages of myeloid and lymphoid cell activation, we herein investigated the role of telomerase reverse transcriptase (TERT), the determining factor of telomerase, in macrophage activation during ALD. In our study, TERT expression and telomerase activity (TA) were remarkably increased in liver tissue of EtOH-fed mice. Moreover, EtOH significantly up-regulated TERT in isolated KCs and RAW 264.7 cells and LPS induced TERT production in vitro. These data indicate that up-regulation of TERT may play a critical role in macrophages during ALD. Furthermore, loss- and gain-of-function studies suggested that TERT switched macrophages towards M1 phenotype by regulating NF-κB signaling, but had limited effect on M2 macrophages polarization in vitro. Additionally, PDTC, a chemical inhibitor of NF-κB, could dramatically down-regulate TERT expression and the hallmarks of M1 macrophages. Therefore, our study unveils the role of TERT in macrophage polarization and the cross-talk between TERT and p65, which may provide a possible explanation for the ethanol-mediated hepatic proinflammatory response and M1 macrophage polarization.
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Wan-Xia
authors.initials: WX
authors.lastname: Li
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Li
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Bao-Ming
authors.initials: BM
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Lv
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.|Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.|Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D016764:Cell Polarity; D025461:Feedback, Physiological; D015870:Gene Expression; D007728:Kupffer Cells / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D019098:Telomerase / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D019098:Telomerase