Epigenetic Regulation of Interleukin 6 by Histone Acetylation in Macrophages and Its Role in Paraquat-Induced Pulmonary Fibrosis.

Lingli Hu,Huijie Huang,Caiyong Yin,Feng Chen,David J R Fulton,Li Hu,Kai Li,Hanting Fan,Yanfang Yu

doi:10.3389/fimmu.2016.00696

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 of IL-6 in 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 of IL-6 in paraquat (PQ)-induced pulmonary fibrosis and to explore whether the epigenetic regulations may play a role in transcriptional regulation of IL-6. In PQ-treated lungs and macrophages, we found that the mRNA and protein expression of IL-6 was robustly increased in a time-dependent and a dose-dependent manner. Our data demonstrated that PQ-induced IL-6 expression in macrophages plays a central role in pulmonary fibrosis through enhanced epithelial-to-mesenchymal transition (EMT). IL-6 expression 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 of IL-6 was enhanced by HDAC inhibitor and blocked by HAT inhibitor. Chromatin immunoprecipitation experiments revealed that HDAC inhibitor increased histones activation marks H3K4me3 and H3K9ac at IL-6 promoter regions. In conclusion, IL-6 functioning through EMT in PQ-induced pulmonary fibrosis was regulated dynamically by HDAC and HAT both in vitro and in vivo via epigenetically regulating chromatin accessibility.

Highlights

Pulmonary fibrosis is a chronic, progressive inflammatory disease of pulmonary interstitial, the occurrence of which is about 1/10,000 and the survival rate is 30–50% at 5 years after diagnosis [1,2,3]
We found that PQ potently increases the mRNA and protein expression of interleukin 6 (IL-6) in a dosedependent manner in the lung and serum following PQ exposure (Figures 1C,D)
We found that PQ could dose-dependently and time-dependently increase IL-6 mRNA expression from lung tissues and macrophages concomitant with the upregulation of protein expression

Summary

Introduction

Pulmonary fibrosis is a chronic, progressive inflammatory disease of pulmonary interstitial, the occurrence of which is about 1/10,000 and the survival rate is 30–50% at 5 years after diagnosis [1,2,3]. The main pathological change associated with this disease is lung interstitial, which is characterized by cell proliferation and extracellular matrix (ECM) excessive accumulation [2, 4]. IL-6 in Paraquat Pulmonary Fibrosis injury, and apoptosis, especially epithelial-to-mesenchymal transition (EMT) may play an important role in the development of pulmonary fibrosis [5,6,7,8]. PQ induced progressive pulmonary fibrosis, the most serious lung damage is often associated with high mortality, appears as early as several days to several weeks after PQ ingestion [12].

Objectives

Methods

Results

Conclusion