Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein E-knockout mice.
OBJECTIVE
To examine the role of the balance between interleukin (IL)-1 and IL-1 receptor antagonist (IL-1Ra) in atherosclerosis and vascular inflammation.


METHODS
Transgenic (Tg) mice overexpressing either secreted IL-1Ra or intracellular IL-1Ra1 as well as IL-1Ra-deficient mice (IL-1Ra -/-) were crossed with apolipoprotein E-deficient mice (ApoE -/-).


RESULTS
In males fed a cholesterol-rich diet for 10 weeks, average atherosclerotic lesion area within aortic roots was significantly decreased in ApoE -/- secreted IL-1Ra Tg (-47%) and ApoE -/- intracellular IL-1Ra1 Tg (-40%) mice as compared to ApoE -/- non-Tg controls. The extent of sudanophilic lesions was reduced within the thoraco-abdominal aorta in ApoE -/- secreted IL-1Ra (-53%) and ApoE -/- intracellular IL-1Ra1 (-67%) Tg mice. In parallel experiments, we observed early mortality and illness among double deficient mice, whereas ApoE -/- IL-1Ra +/+ and ApoE +/+ IL-1Ra -/- mice were apparently healthy. After 7 weeks of diet, ApoE -/- IL-1Ra -/- mice exhibited massive aortic inflammation with destruction of the vascular architecture, but no signs of atherosclerosis. ApoE -/- IL-1Ra +/+ had atherosclerosis and a moderate inflammatory reaction, whereas ApoE +/+ IL-1Ra -/- mice were free of vascular lesions. Macrophages were present in large amounts within inflammatory lesions in the adventitia of ApoE -/- IL-1Ra -/- mice.


CONCLUSIONS
Our results demonstrate that the IL-1/IL-1Ra ratio plays a critical role in the pathogenic mechanisms leading to vascular inflammation and atherosclerosis in ApoE -/- mice.
Merhi-Soussi
Faten
F
Division of Rheumatology, Department of Internal Medicine, University Hospital of Geneva, Switzerland.
Kwak
Brenda R
BR
Magne
David
D
Chadjichristos
Christos
C
Berti
Marina
M
Pelli
Graziano
G
James
Richard W
RW
Mach
François
F
Gabay
Cem
C
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000276:immunology* / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000032:analysis
D001057:Apolipoproteins E; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D000685:Serum Amyloid A Protein; D002784:Cholesterol