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Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice.


ABSTRACT: 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.The aim of this study was to test the role of IL-27 receptor signaling in immune cells in atherosclerosis development.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.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.

SUBMITTER: Koltsova EK 

PROVIDER: S-EPMC3750996 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice.

Koltsova Ekaterina K EK   Kim Gisen G   Lloyd Kathleen M KM   Saris Christiaan J M CJ   von Vietinghoff Sibylle S   Kronenberg Mitchell M   Ley Klaus K  

Circulation research 20120827 10


<h4>Rationale</h4>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 elevat  ...[more]

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