Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy

Abstract

It has recently been appreciated that atherosclerosis is predominantly an inflammatory process. Atherosclerosis begins with a fatty streak, which is made up almost entirely of monocyte-derived macrophages. The development of an atheroma continues as T-cells, mast cells, and other inflammatory cells are recruited to the intima. This collection of inflammatory cells promotes smooth muscle cell replication and extracellular matrix elaboration, thereby increasing the lesion size. Various studies have highlighted that interleukin-6 (IL-6) is an upstream inflammatory cytokine that plays a central role in propagating the downstream inflammatory response responsible for atherosclerosis. IL-6 release is stimulated by acute infections, chronic inflammatory conditions, obesity, and physiologic stress. The high level of IL-6 found in such conditions has a myriad of functions, including hepatic synthesis of acute-phase reactants, activation of endothelial cells, increased coagulation, activation of the hypothalamic-pituitary-adrenal axis, and promotion of lymphocyte proliferation and differentiation. Considering the importance of IL-6 in the development of coronary artery disease, targeting its actions could prove to be beneficial. Individuals with a variant in the IL-6 receptor that impairs classic IL-6 signaling were found to have a decreased risk for coronary heart disease. Tocilizumab is a monoclonal antibody that targets the IL-6 receptor and has been show to alleviate symptoms in patients with rheumatoid arthritis, a disease largely driven by the proinflammatory actions of IL-6. Therefore, further studies are needed to determine the role of tocilizumab and other IL-6 receptor blockers in decreasing the inflammatory response key in the development of atherosclerosis.