Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis

• Published in: Circulation (New York, N.Y.) Vol. 110; no. 22; pp. 3493 - 3500
• Main Authors: Schieffer, Bernhard, Selle, Tina, Hilfiker, Andres, Hilfiker-Kleiner, Denise, Grote, Karsten, Tietge, Uwe J F, Trautwein, Christian, Luchtefeld, Maren, Schmittkamp, Christian, Heeneman, Sylvia, Daemen, Mat J A P, Drexler, Helmut
• Format: Journal Article
• Language: English
• Published: United States 30.11.2004
• Subjects: Animals; Aortic Diseases - etiology; Aortic Diseases - pathology; Aortic Diseases - physiopathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arteriosclerosis - etiology; Arteriosclerosis - pathology; Arteriosclerosis - physiopathology; Blood Pressure; Collagen - analysis; Homeostasis; Hyperlipoproteinemia Type II - complications; Hyperlipoproteinemia Type II - genetics; Hyperlipoproteinemia Type II - physiopathology; Interleukin-6 - blood; Interleukin-6 - deficiency; Interleukin-6 - genetics; Interleukin-6 - physiology; Leukocytes - pathology; Macrophages - pathology; Male; Matrix Metalloproteinase 9 - analysis; Mice; Mice, Inbred C57BL; Mice, Knockout; Vasculitis - etiology; Vasculitis - pathology; Vasculitis - physiopathology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.0000148135.08582.97

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. 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. 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.