Abstract 17750: Interleukin-1 Receptor type-1 on Vascular Wall Cells is the Target for the Pro-Atherogenic Effects of Bone Marrow-Derived Interleukin-1α and Interleukin-1β in Apolipoprotein E-Deficient Mice
Introduction: Vascular and bone marrow-derived cells produce IL-1α and IL-1β that exert pro-inflammatory effects in these cell types by binding to type-1 IL-1 receptor (IL-1RI). While IL-1β was shown to be pro-atherogenic, the role of IL-1α in atherogenesis is less defined and it is not clear which cell type is the main target for the pro-atherogenic effects of IL−1.
Objectives and Methods: We generated apoE−/−/IL-1α−/−; apoE−/−/IL-1β−/− and apoE−/−/IL-1RI−/− mice and created radiation chimeras in order to: I. Investigate whether IL-1α and IL-1β from bone marrow-derived cells promote the development of atherosclerosis. II. To study whether IL-1RI on vascular wall resident or bone marrow-derived cells mediates the pro-atherogenic effects of IL−1.
Results: Aortic sinus lesion area was ∼50% lower in apoE−/−/IL-1α−/− and apoE−/−/IL-1β−/− compared to apoE−/− mice despite higher non-HDL cholesterol levels. Lesion area in apoE−/− mice transplanted with IL-1β−/− or IL-1α−/− cells was 32% and 52% lower than IL-1+/+ transplanted mice. Isolated IL-1α−/− macrophages from atherosclerotic mice secreted lower levels of the pro-inflammatory cytokine IL-1β and higher levels of the anti-inflammatory cytokine IL−10. Whole body deficiency of IL-1RI inhibited atherogenesis in apoE−/− mice (20%-47% reduction in aortic sinus lesion area in three experiments). mRNA levels of CD68, VCAM-1, ICAM-1 and MCP-1 were lower in aorta from apoE−/−/IL-1RI−/− compared to apoE−/− mice. apoE−/−/IL-1RI−/− mice transplanted with IL-1RI+/+ bone marrow-derived cells had reduced (48%) aortic sinus lesion compared to apoE−/− mice while specific deficiency of IL-1RI in bone marrow-derived cells did not reduce atherosclerosis in apoE−/− mice. Finally, specific blockade of IL-1RI resulted in complete abrogation of IL-1β-induced expression of adhesion and chemotactic molecules in isolated Human Umbilical Vein Endothelial Cells (HUVEC).
Conclusion: The results suggest that IL-1α and IL-1β from bone marrow-derived cells promote the development of atherosclerosis and that vascular wall resident cells are the main target for the pro-atherogenic effects of IL-1 through IL-1RI, possibly by induction of adhesion and chemotactic molecules in endothelial cells.
- © 2010 by American Heart Association, Inc.