Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α

被引:108
作者
Kamari, Yehuda [1 ,2 ]
Shaish, Aviv [1 ]
Shemesh, Shay [1 ,3 ]
Vax, Einav [1 ,2 ]
Grosskopf, Itamar [1 ,2 ]
Dotan, Shahar [4 ]
White, Malka [4 ]
Voronov, Elena [4 ]
Dinarello, Charles A. [5 ]
Apte, Ron N. [4 ]
Harats, Dror [1 ,2 ]
机构
[1] Chaim Sheba Med Ctr, Bert Strassburger Lipid Ctr, IL-52621 Tel Hashomer, Israel
[2] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel
[3] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52100 Ramat Gan, Israel
[4] Ben Gurion Univ Negev, Shraga Segal Dept Microbiol & Immunol, IL-84105 Beer Sheva, Israel
[5] Univ Colorado Denver, Dept Med, Aurora, CO USA
关键词
Atherosclerosis; IL-1; Macrophages; Cytokines; ApoE-deficient mice; IL-1 RECEPTOR ANTAGONIST; TUMOR-NECROSIS-FACTOR; CHOLESTEROL LEVEL; ENDOTHELIAL-CELLS; GENE-EXPRESSION; ATHEROGENESIS; IL-1-ALPHA; PROTEIN; ALPHA; BETA;
D O I
10.1016/j.bbrc.2011.01.008
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
Objective: Interleukin (IL)-1 alpha and IL-1 beta are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1 beta, the role of IL-1 alpha in atherogenesis remains unclear. We assessed whether IL-1 alpha and IL-1 beta from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1 alpha or IL-1 beta deficiency on degradation of LDL and cytokine production. Methods: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1 alpha-/- and apoE-/-/IL-1 beta-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1 alpha-/- and apoE-/-/IL-1 beta-/-. Results: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1 alpha or IL-1 beta in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1 beta-/- or IL-1 alpha-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1 alpha-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNF alpha and IL-12 similarly to IL-1+/+ macrophages; however, IL-1 alpha deficient macrophages secreted reduced levels of IL-1 beta (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. Conclusion: We show for the first time that it is IL-1 alpha from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1 alpha in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:197 / 203
页数:7
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