Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis.
BACKGROUND
Vascular lipid accumulation and inflammation are hallmarks of atherosclerosis and perpetuate atherosclerotic plaque development. Mediators of inflammation, ie, interleukin (IL)-6, are elevated in patients with acute coronary syndromes and may contribute to the exacerbation of atherosclerosis.


RESULTS
To assess the role of IL-6 in atherosclerosis, ApoE-/--IL-6-/- double-knockout mice were generated, fed a normal chow diet, and housed for 53+/-4 weeks. Mortality and blood pressure were unaltered. However, serum cholesterol levels and subsequent atherosclerotic lesion formation (oil red O stain) were significantly increased in ApoE-/--IL-6-/- mice compared with ApoE-/-, wild-type (WT), and IL-6-/- mice. Plaques of ApoE-/--IL-6-/- mice showed significantly reduced transcript and protein levels of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, collagen I and V, and lysyl oxidase (by reverse transcriptase-polymerase chain reaction and immunohistochemistry). Recruitment of macrophages and leukocytes (Mac3- and CD45-positive staining) into the atherosclerotic lesion was significantly reduced in ApoE-/--IL-6-/- mice. The transcript and serum protein (ELISA) levels of IL-10 were significantly reduced.


CONCLUSIONS
Thus, a lifetime IL-6 deficiency enhances atherosclerotic plaque formation in ApoEK-/--IL-6-/- mice and leads to maladaptive vascular developmental processes. These observations are consistent with the notion that baseline levels of IL-6 are required to modulate lipid homeostasis, vascular remodeling, and plaque inflammation in atherosclerosis.
Schieffer
Bernhard
B
Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany. schieffer.bernhard@mh-hannover.de
Selle
Tina
T
Hilfiker
Andres
A
Hilfiker-Kleiner
Denise
D
Grote
Karsten
K
Tietge
Uwe J F
UJ
Trautwein
Christian
C
Luchtefeld
Maren
M
Schmittkamp
Christian
C
Heeneman
Sylvia
S
Daemen
Mat J A P
MJ
Drexler
Helmut
H
D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D001794:Blood Pressure; D003094:Collagen / Q000032:analysis; D006706:Homeostasis; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D015850:Interleukin-6 / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014657:Vasculitis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*
D001057:Apolipoproteins E; D015850:Interleukin-6; D003094:Collagen; D020780:Matrix Metalloproteinase 9