IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14).

Abstract

OBJECTIVE:

IL-35 (interleukin-35) is an anti-inflammatory cytokine, which inhibits immune responses by inducing regulatory T cells and regulatory B cells and suppressing effector T cells and macrophages. It remains unknown whether atherogenic stimuli induce IL-35 and whether IL-35 inhibits atherogenic lipid-induced endothelial cell (EC) activation and atherosclerosis. EC activation induced by hyperlipidemia stimuli, including lysophosphatidylcholine is considered as an initiation step for monocyte recruitment and atherosclerosis. In this study, we examined the expression of IL-35 during early atherosclerosis and the roles and mechanisms of IL-35 in suppressing lysophosphatidylcholine-induced EC activation.

APPROACH AND RESULTS:

Using microarray and ELISA, we found that IL-35 and its receptor are significantly induced during early atherosclerosis in the aortas and plasma of ApoE (apolipoprotein E) knockout mice-an atherosclerotic mouse model-and in the plasma of hypercholesterolemic patients. In addition, we found that IL-35 suppresses lysophosphatidylcholine-induced monocyte adhesion to human aortic ECs. Furthermore, our RNA-sequencing analysis shows that IL-35 selectively inhibits lysophosphatidylcholine-induced EC activation-related genes, such as ICAM-1 (intercellular adhesion molecule-1). Mechanistically, using flow cytometry, mass spectrometry, electron spin resonance analyses, and chromatin immunoprecipitation-sequencing analyses, we found that IL-35 blocks lysophosphatidylcholine-induced mitochondrial reactive oxygen species, which are required for the induction of site-specific H3K14 (histone 3 lysine 14) acetylation, increased binding of proinflammatory transcription factor AP-1 in the promoter of ICAM-1, and induction of ICAM-1 transcription in human aortic EC. Finally, IL-35 cytokine therapy suppresses atherosclerotic lesion development in ApoE knockout mice.

CONCLUSIONS:

IL-35 is induced during atherosclerosis development and inhibits mitochondrial reactive oxygen species-H3K14 acetylation-AP-1-mediated EC activation.

• Authors: Xinyuan Li, Ying Shao, Xiaojin Sha, Pu Fang, Yin-Ming Kuo, Andrew J Andrews, Yafeng Li, William Y Yang, Massimo Maddaloni, David W Pascual, Jin J Luo, Xiaohua Jiang, Hong Wang, Xiaofeng Yang
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 38 Issue 3 Pg. 599-609 (03 2018) ISSN: 1524-4636 [Electronic] United States
• PMID: 29371247 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2018 American Heart Association, Inc.

Chemical References

• Histones
• ICAM1 protein, human
• Interleukins
• Lysophosphatidylcholines
• Reactive Oxygen Species
• Receptors, Interleukin
• Transcription Factor AP-1
• interleukin 35 receptor, mouse
• interleukin-35, human
• interleukin-35, mouse
• Intercellular Adhesion Molecule-1
• Lysine

Topics

• Acetylation
• Animals
• Aorta (drug effects, metabolism, pathology)
• Aortic Diseases (genetics, metabolism, pathology, prevention & control)
• Atherosclerosis (genetics, metabolism, pathology, prevention & control)
• Cells, Cultured
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism, pathology)
• Female
• Histones (metabolism)
• Humans
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Interleukins (metabolism, pharmacology)
• Lysine
• Lysophosphatidylcholines (pharmacology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• Mitochondria (drug effects, metabolism, pathology)
• Protein Processing, Post-Translational
• Reactive Oxygen Species (metabolism)
• Receptors, Interleukin (genetics, metabolism)
• Transcription Factor AP-1 (genetics, metabolism)