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. Methods and 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 ApoE(-/-) - 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.