Abstract 5067: Interleukin-7 is an Active Participant in Atherogenesis by Promoting Monocyte/macrophage Arrest on Endothelial Cells
Atherosclerosis is a chronic inflammatory disease, but can regress. Despite the importance of atherosclerotic lesion regression, its mechanisms are not well understood. We induced regression of advanced atherosclerosis in Apoe−/− mice and studied potential mechanisms. A single i.v. injection of helper-dependent adenoviral vector expressing human apoE3 (HDAd-gE3) into Apoe−/− mice resulted in a 28±4% reduction of the advanced atherosclerosis (n= 7 vs. baseline n=8, p=0.012) after 41 weeks. Using this system, we analyzed gene expression profiles in the aorta at day 10, when plasma cholesterol was normalized. Pathway and ontology analyses revealed multiple signaling pathways influenced by the treatment; however, after correction for multiple testing we unexpectedly found that interleukin-7 (IL-7) was significantly downregulated. IL-7 is a nonredundant cytokine for B- and T-cell development. Although several studies have suggested that IL-7 is associated with cardiovascular disease, IL-7 has not been implicated as having a direct role in atherogenesis. IL-7 positive areas in the aorta were also reduced in the HDAd-gE3 group by 53% (n=5– 6/group, p<0.01) after 41 weeks of treatment. IL-7 could be a marker for lesion regression or reduced inflammation, or be directly involved in atherosclerosis. To test this hypothesis, we analyzed the effects of IL-7 on expression of adhesion molecules and chemokines in human aortic endothelial cells (HAECs). IL-7 upregulated adhesion molecules and chemokines which include VCAM-1, ICAM-1, E-selectin and monocyte chemotactic protein-1. This upregulation was time- and dose-dependent and promoted monocyte adhesion to HAECs. Moreover, the increase of plasma IL-7 levels in Apoe−/− mice by HDAd-IL-7 enhanced homing of monocyte/macrophage to the lesions by 2-fold (n=6/group, p<0.01) without increasing plasma cholesterol. In contrast, transplantation of bone marrow cells isolated from Il-7−/− mice into Ldlr−/− mice reduced macrophage positive areas by 26% after 20 weeks compared with those isolated from wild type mice (n=6/group, p<0.05). These results suggest that IL-7 plays a direct role in atherosclerosis by promoting monocyte/macrophage homing to atherosclerotic lesions.