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 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.