title: Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α.
abstract: OBJECTIVE
  Interleukin (IL)-1α and IL-1β 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-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β 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-1α or IL-1β deficiency on degradation of LDL and cytokine production.
  
  
  METHODS
  We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-.
  
  
  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-1α or IL-1β 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-1β-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10.
  
  
  CONCLUSIONS
  We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.
authors.affiliation: The Bert Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer, Israel. yehuda.kamari@sheba.health.gov.il
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Kamari
authors.forename: Aviv
authors.initials: A
authors.lastname: Shaish
authors.forename: Shay
authors.initials: S
authors.lastname: Shemesh
authors.forename: Einav
authors.initials: E
authors.lastname: Vax
authors.forename: Itamar
authors.initials: I
authors.lastname: Grosskopf
authors.forename: Shahar
authors.initials: S
authors.lastname: Dotan
authors.forename: Malka
authors.initials: M
authors.lastname: White
authors.forename: Elena
authors.initials: E
authors.lastname: Voronov
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Ron N
authors.initials: RN
authors.lastname: Apte
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors*; D005487:Foam Cells / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D053582:Interleukin-1alpha; D053583:Interleukin-1beta