title: Epigenetic Regulation of Interleukin 6 by Histone Acetylation in Macrophages and Its Role in Paraquat-Induced Pulmonary Fibrosis.
abstract: Overexpression of interleukin 6 (IL-6) has been proposed to contribute to pulmonary fibrosis and other fibrotic diseases. However, the regulatory mechanisms and the role ofIL-6in fibrosis remain poorly understood. Epigenetics refers to alterations of gene expression without changes in the DNA sequence. Alternation of chromatin accessibility by histone acetylation acts as a critical epigenetic mechanism to regulate various gene transcriptions. The goal of this study was to determine the impact ofIL-6in paraquat (PQ)-induced pulmonary fibrosis and to explore whether the epigenetic regulations may play a role in transcriptional regulation ofIL-6. In PQ-treated lungs and macrophages, we found that the mRNA and protein expression ofIL-6was robustly increased in a time-dependent and a dose-dependent manner. Our data demonstrated that PQ-inducedIL-6expression in macrophages plays a central role in pulmonary fibrosis through enhanced epithelial-to-mesenchymal transition (EMT).IL-6expression and its role to enhance PQ-induced pulmonary fibrosis were increased by histone deacetylase (HDAC) inhibition and prevented by histone acetyltransferase (HAT) inhibition. In addition, the ability of CRISPR-ON transcription activation system (CRISPR-ON) to promote transcription ofIL-6was enhanced by HDAC inhibitor and blocked by HAT inhibitor. Chromatin immunoprecipitation experiments revealed that HDAC inhibitor increased histones activation marks H3K4me3 and H3K9ac atIL-6promoter regions. In conclusion,IL-6functioning through EMT in PQ-induced pulmonary fibrosis was regulated dynamically by HDAC and HAT bothin vitroandin vivo viaepigenetically regulating chromatin accessibility.
authors.affiliation: Department of Forensic Medicine, Nanjing Medical University , Nanjing , China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Forensic Medicine, Nanjing Medical University , Nanjing , China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Forensic Medicine, Nanjing Medical University , Nanjing , China.
authors.forename: Huijie
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Forensic Medicine, Nanjing Medical University , Nanjing , China.
authors.forename: Hanting
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Forensic Medicine, Nanjing Medical University , Nanjing , China.
authors.forename: Li
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Forensic Medicine, Nanjing Medical University , Nanjing , China.
authors.forename: Caiyong
authors.initials: C
authors.lastname: Yin
authors.affiliation: Department of Forensic Medicine, Nanjing Medical University , Nanjing , China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Vascular Biology Center, Augusta University, Augusta, GA, USA; Department of Pharmacology, Augusta University, Augusta, GA, USA.
authors.forename: David J R
authors.initials: DJ
authors.lastname: Fulton
authors.affiliation: Department of Forensic Medicine, Nanjing Medical University, Nanjing, China; Vascular Biology Center, Augusta University, Augusta, GA, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
keywords: IL-6; epigenetics; forensic toxicology; histone acetylation; paraquat; pulmonary fibrosis