title: Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the pro-atherogenic effects of interleukin-1 in apoE-deficient mice.
abstract: OBJECTIVE
  Interleukin (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.
  
  
  RESULTS
  We generated apoE-/-/IL-1R1-/- 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-1R1-/- 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).
  
  
  CONCLUSIONS
  Vascular 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.
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Shemesh
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Kamari
authors.forename: Aviv
authors.initials: A
authors.lastname: Shaish
authors.forename: Sarita
authors.initials: S
authors.lastname: Olteanu
authors.forename: Michal
authors.initials: M
authors.lastname: Kandel-Kfir
authors.forename: Tal
authors.initials: T
authors.lastname: Almog
authors.forename: Itamar
authors.initials: I
authors.lastname: Grosskopf
authors.forename: Ron N
authors.initials: RN
authors.lastname: Apte
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001835:Body Weight; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D011828:Radiation Chimera; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D007375:Interleukin-1; D008055:Lipids; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I