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Interleukin-7 promotes monocyte/macrophage arrest on endothelial cells

ABSTRACT: Background: It is recognized that atherosclerosis can regresses at least in animal models. However, little is known about the mechanisms. We induced regression of advanced atherosclerosis in apolipoprotein E deficient (APOE/) mice and studied underlying mechanisms. Unexpectedly, our study led to the role of interleukin-7 (IL-7) in atherogenesis. Methods and Results: We treated APOE/ mice fed a high cholesterol diet for 30 weeks to induce advanced lesions with a helper-dependent adenoviral vector expressing human apoE3 (HDAd-gE3), and analyzed the regression of atherosclerosis after 41 weeks. Using microarray analysis, we identified IL-7 as one of most significantly affected genes by lowering cholesterol. To answer why IL-7 is downregulated by reduced cholesterol, we studied effects of IL-7 on endothelial cells (ECs). Our major findings were (1) long-term lowering cholesterol induced regression of advanced atherosclerosis. (2) Microarray analysis identified multiple signaling pathways affected by lowering cholesterol. (3) Correction for multiple testing revealed that IL-7 expression was downregulated, whereas gamma-sarcoglycan and Î±-actin were upregulated. (4) Oxidized LDL upregulated IL-7 expression in macrophages but not in aorta ECs or smooth muscle cells. (5) IL-7 increased the expression of cell adhesion molecules and chemokine in ECs and promoted monocyte adhesion to ECs. (6) Systemic elevation of IL-7 induced inflammatory response and recruited monocyte/macrophage to the lesions without increasing plasma cholesterol. Conclusion: Our finding suggest that IL-7 inflames endothelium and triggers the adhesion/recruitment of monocyte/macrophages to the atherosclerotic lesions and thus plays a direct role in development of atherosclerosis. Key Words: arteriosclerosis, gene therapy, hypercholesterolemia, interleukins, cell adhesion molecules

ORGANISM(S): Mus musculus

PROVIDER: GSE15914 | GEO | 2009/10/01

SECONDARY ACCESSION(S): PRJNA116913

REPOSITORIES: GEO

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Project description:Background: It is recognized that atherosclerosis can regresses at least in animal models. However, little is known about the mechanisms. We induced regression of advanced atherosclerosis in apolipoprotein E deficient (APOE/) mice and studied underlying mechanisms. Unexpectedly, our study led to the role of interleukin-7 (IL-7) in atherogenesis. Methods and Results: We treated APOE/ mice fed a high cholesterol diet for 30 weeks to induce advanced lesions with a helper-dependent adenoviral vector expressing human apoE3 (HDAd-gE3), and analyzed the regression of atherosclerosis after 41 weeks. Using microarray analysis, we identified IL-7 as one of most significantly affected genes by lowering cholesterol. To answer why IL-7 is downregulated by reduced cholesterol, we studied effects of IL-7 on endothelial cells (ECs). Our major findings were (1) long-term lowering cholesterol induced regression of advanced atherosclerosis. (2) Microarray analysis identified multiple signaling pathways affected by lowering cholesterol. (3) Correction for multiple testing revealed that IL-7 expression was downregulated, whereas gamma-sarcoglycan and Î±-actin were upregulated. (4) Oxidized LDL upregulated IL-7 expression in macrophages but not in aorta ECs or smooth muscle cells. (5) IL-7 increased the expression of cell adhesion molecules and chemokine in ECs and promoted monocyte adhesion to ECs. (6) Systemic elevation of IL-7 induced inflammatory response and recruited monocyte/macrophage to the lesions without increasing plasma cholesterol. Conclusion: Our finding suggest that IL-7 inflames endothelium and triggers the adhesion/recruitment of monocyte/macrophages to the atherosclerotic lesions and thus plays a direct role in development of atherosclerosis. Key Words: arteriosclerosis, gene therapy, hypercholesterolemia, interleukins, cell adhesion molecules Female APOE-/- mice (8 weeks of age) on a C57BL/6 background were purchased from Jackson Laboratory and were fed a diet containing 0.2% (w/w) cholesterol and 10% (v/w) coconut oil to induce atherosclerosis for 30 weeks. Mice were then divided into 3 groups, (n=15/group), treated with a tail vein injection of helper-dependent adenovirus expressing human apolipoprotein E3 (HDAd-gE3, 5 x 1012 viral particles/kg, n=11, vector), empty vector (HDAd-0, 5 x 1012 VP/kg, n=11, vector control) or phosphate buffered saline (PBS, vehicle) and sacrificed 10 days after. Three aortas extending sinus to arch were pooled for RNA extraction with an RNeasy kit (Qiagen). Sample ID 12031: E4: vector control (HDAd-0) 12043: E5: vector control 12046: V2: vector 12047: V3: vector 12048: V4: vector 12051: B1: vehicle (PBS) 12053: B3: vehicle 12054: B4: vehicle 12039: E3: vector control

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Interleukin-7 promotes monocyte/macrophage arrest on endothelial cells

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