title: Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice.
abstract: BACKGROUND
  Atherosclerosis is a chronic inflammatory disease of the arterial wall. Several proinflammatory cytokines are known to promote atherosclerosis, but less is known about the physiological role of anti-inflammatory cytokines. Interleukin (IL)-27 is a recently discovered member of the IL-6/IL-12 family. The IL-27 receptor is composed of IL-27 receptor A (WSX-1) and gp130 and is required for all established IL-27 signaling pathways. The expression of the IL-27 subunit Ebi3 is elevated in human atheromas, yet its function in atherosclerosis remains unknown.
  
  
  OBJECTIVE
  The aim of this study was to test the role of IL-27 receptor signaling in immune cells in atherosclerosis development.
  
  
  RESULTS
  Atherosclerosis-prone Ldlr(-/-) mice transplanted with Il27ra(-/-) bone marrow and fed Western diet for 16 weeks developed significantly larger atherosclerotic lesions in aortic roots, aortic arches, and abdominal aortas. Augmented disease correlated with increased accumulation of CD45(+) leukocytes and CD4(+) T cells in the aorta, which produced increased amounts of IL-17A and tumor necrosis factor. Several chemokines, including CCL2, were upregulated in the aortas of Ldlr(-/-) mice receiving Il27ra(-/-) bone marrow, resulting in accumulation of CD11b(+) and CD11c(+) macrophages and dendritic cells in atherosclerotic aortas.
  
  
  CONCLUSIONS
  The absence of anti-inflammatory IL-27 signaling skews immune responses toward T-helper 17, resulting in increased production of IL-17A and tumor necrosis factor, which in turn enhances chemokine expression and drives the accumulation of proatherogenic myeloid cells in atherosclerotic aortas. These findings establish a novel antiatherogenic role for IL-27 receptor signaling, which acts to suppress the production of proinflammatory cytokines and chemokines and to curb the recruitment of inflammatory myeloid cells into atherosclerotic aortas.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. ekoltsova@liai.org
authors.forename: Ekaterina K
authors.initials: EK
authors.lastname: Koltsova
authors.forename: Gisen
authors.initials: G
authors.lastname: Kim
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Lloyd
authors.forename: Christiaan J M
authors.initials: CJ
authors.lastname: Saris
authors.forename: Sibylle
authors.initials: S
authors.lastname: von Vietinghoff
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000276:immunology / Q000378:metabolism; D001011:Aorta / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism*; D018123:Receptors, Interleukin; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D039521:CD11c Antigen; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C098680:Il17a protein, mouse; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha