Abstract 211: IL-35 Suppresses Endothelial Cell Activation by Inhibiting Histone H3K14 Acetylation and AP-1
Background: IL-35 is a newly identified anti-inflammatory cytokine, which inhibits inflammation and immune responses by inducing regulatory T cells and regulatory B cells and suppressing effector T cells and macrophages. We previously reported that IL-35 is a responsive cytokine that is not constitutively expressed in human tissues, but can be induced by proinflammatory stimuli in vascular endothelial cells (EC), smooth muscle cells and monocytes. However, the functions of IL-35 on non-lymphocytes such as vascular EC remain unknown. EC activation induced by proatherogenic stimuli including lysophosphatidylcholine (LPC) is considered as the initiation step of monocyte recruitment and atherosclerosis. In this study, we examined the expression of IL-35 during early atherosclerosis and the role of IL-35 in LPC-induced EC activation.
Methods and Results: Using microarray method, we found that two IL-35 subunits and their receptor subunits are all significantly induced during early atherosclerosis in the aortas of atherosclerotic mouse model, apolipoprotein E (ApoE) knockout mice fed with 3 weeks of high fat diet. In addition, we found that IL-35 can suppress LPC-induced monocyte adhesion to human aortic ECs (HAEC). Mechanistic, our analysis using EC biology gene array shows that IL-35 selectively inhibits LPC-induced expressions of EC adhesion molecules ICAM-1, VCAM-1, and proinflammatory cytokine IL-1β in human aortic EC (HAEC). To further dissect the molecular mechanisms underlying the IL-35 inhibitory effects on LPC-induced EC activation gene upregulation, we performed mass spectrum analysis and electrophoretic mobility shift assay. We found that IL-35 blocked LPC-induced histone H3 lysine 14 (H3K14) acetylation as well as the binding of pro-inflammatory transcription factor AP-1 to the promoters of EC adhesion molecules in HAEC.
Conclusions: IL-35 is induced in the aortas during early atherogenesis and suppresses human EC activation and monocyte adhesion by inhibiting histone acetylation and AP-1 nuclear translocation.
Author Disclosures: X. Li: None. P. Fang: None. X. Sha: None. Y. Li: None. Y. Kuo: None. A.J. Andrews: None. H. Wang: None. X. Yang: None.
- © 2015 by American Heart Association, Inc.