Aernoud Fiolet

19 General introduction and thesis outline SMALL-SIZED BUT CRUCIAL ACTORS: CYTOKINES Not surprisingly, inflammatory mediators that play important roles in autoimmunological pathologies and proliferative conditions are also seen at higher concentrations in and around atherothrombotic lesions. There are several families of inflammatory mediators all with both pro- inflammatory and anti-inflammatory subsets: chemokines, growth factors, and most notably cytokines. More than 60 different cytokines have been described. Divided into several families, the interleukin family encompasses the largest subset of cytokines, next to tumour necrosis factor and interferons. 38 Cytokines enable communication between leukocytes as well as endothelium and vascular smooth muscle cells in autocrine, paracrine, and endocrine ways. 39 In vivo and in vitro data have revealed cytokines with pro- and anti-inflammatory properties, in balanced equilibrium in physiological circumstances. Important pro- inflammatory cytokines include interleukin – 1, interleukin – 6, tumour necrosis factor α , and interferon - γ . Important anti-inflammatory cytokines include interleukin – 10 and transforming growth factor β . They are regarded as anti- inflammatory and are secreted by M2 macrophages. They induce atheroregression using complex and not fully understood mechanisms. 40 Interleukin – 6 Two cytokines, interleukin – 1 and interleukin – 6, have been shown to play a particularly important role in atherothrombosis. Interleukin – 6 levels are increased relative to the systemic concentration around ruptured plaques, and human atherosclerotic plaques have increased gene expression for interleukin – 6. 41,42 Interleukin – 6 plays a pivotal role in immunology, since it has a direct effect on leukocyte recruitment byendothelial cells and amplifies the inflammatory response by inducing chemokine release. 43 The observation that interleukin – 6 is necessary for the recruitment of inflammatory cells in atherosclerotic plaque was confirmed in several atherosclerosis mouse models. Exogenous elevated levels of interleukin – 6 by the administration of recombinant interleukin – 6 in obese mice increases atherosclerotic plaques and increases other inflammatory mediators, such as tumour necrosis factor- α and interleukin – 1. In addition, blocking trans-signaling of interleukin – 6 in mice reduces monocyte infiltration and atherosclerotic plaque progression. 44 However, interleukin – 6