کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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5948163 | 1172377 | 2012 | 8 صفحه PDF | دانلود رایگان |
ObjectivesInterleukin (IL)-1 produced by vascular and bone marrow-derived cells exerts proinflammatory effects in these cell types by binding to IL-1 receptor type-1 (IL-1R1). We have previously shown that bone marrow-derived IL-1α and IL-1β are critical for atherogenesis in apoE knockout (KO) mice. The aim of the present study was to investigate whether IL-1R1 on vascular wall resident or bone marrow-derived cells mediates IL-1's effects in atherogenesis.Methods and resultsWe generated apoEâ/â/IL-1R1â/â double knockout (DKO) mice and created radiation chimeras. Aortic sinus lesion area was 20-47% lower in DKO compared to apoE KO mice with similar plasma lipids. The production of IL-1α and IL-1β upon stimulation with LPS was not altered in IL-1R1â/â compared to IL-1R1+/+ peritoneal macrophages. DKO mice transplanted with IL-1R1+/+ bone marrow-derived cells had reduced (48%) aortic sinus lesion compared to apoE KO mice while specific deficiency of IL-1R1 in bone marrow-derived cells did not attenuate atherosclerosis. The mRNA levels of genes that promote macrophage recruitment to the vascular wall, namely CD68, VCAM-1, ICAM-1 and MCP-1 were lower in aortas from DKO compared to apoE KO mice. Finally, blockade of IL-1R1 with IL-1R antagonist (IL-1Ra) resulted in complete abrogation of IL-1β-induced expression of adhesion and chemotactic molecules and IL-1α, in isolated human umbilical vein endothelial cells (HUVEC).ConclusionsVascular wall resident cells are the main targets for the pro-atherogenic effects of bone marrow-derived IL-1 through IL-1R1, partly by induction of adhesion and chemotactic molecules in endothelial cells.
⺠We generated apoE/IL-1R1 double knockout (DKO) mice. ⺠IL-1R1 deficiency in bone marrow-derived cells did not attenuate atherosclerosis. ⺠DKO transplanted with IL-1R1+/+ cells had reduced lesion area compared to apoE KO. ⺠Aortas from DKO had lower mRNA levels of inflammatory genes compared to apoE KO. ⺠IL-1R1 blockade inhibited endothelial cell activation in HUVEC.
Journal: Atherosclerosis - Volume 222, Issue 2, June 2012, Pages 329-336