Journal Article

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability

He, Shaolin, Wang, Boyuan, Liu, Jing, Wu, Chun, Dong, Nianguo, Liu, Jie, Lin, Jibin, Duan, Yanping, Shan, Shengshuai, Yang, Keping, Li, Dazhu, Liu, Tianxiao, Huang, Kai, Ji, Qingwei

2018

Overview

Background/Aims: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. Methods: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. Results: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4 + T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. Conclusion: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.

• Publisher: S. Karger AG,Cell Physiol Biochem Press GmbH & Co KG
• Subject: Animals / Antibodies, Neutralizing - immunology / Apolipoproteins E - deficiency / Apolipoproteins E - genetics / Apoptosis / Apoptosis - drug effects / Atherosclerosis / Atherosclerosis - metabolism / Atherosclerosis - pathology / Atherosclerosis - prevention & control / CD4-Positive T-Lymphocytes - cytology / CD4-Positive T-Lymphocytes - metabolism / Cells, Cultured / Collagen degradation / Cytokines / Cytokines - analysis / Dendritic cells / Disease / Ethics / Experiments / Gene expression / Humans / Hydrogen Peroxide - toxicity / IL-37 / Interleukin-1 - genetics / Interleukin-1 - metabolism / Interleukin-18 Receptor alpha Subunit - genetics / Interleukin-18 Receptor alpha Subunit - immunology / Interleukin-18 Receptor alpha Subunit - metabolism / Kinases / Laboratory animals / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Muscle, Smooth, Vascular - cytology / Muscle, Smooth, Vascular - metabolism / Original Paper / Plaque, Atherosclerotic - metabolism / Proteins / Rodents / Smad3 Protein - deficiency / Smad3 Protein - genetics / Smooth muscle / Smooth muscle cell apoptosis / T cell differentiation