Aernoud Fiolet

20 Chapter 1 deficient atherosclerotic-prone mice models have lower inflammatory cell influx but increased lipid deposition and atherosclerotic plaque formation, underscoring an initially protective role of the inflammatory response in lipid accumulation. 45,46 Complementary to the animal studies are epidemiological observations of interleukin – 6. Elevated concentrations of interleukin – 6 are associated with an increased risk of major adverse cardiovascular events, even when corrected for traditional cardiovascular risk factors known to influence circulating interleukin–6, such as adiposity and smoking. 47,48 Interleukin – 1 In similar ways to interleukin – 6, a strong association between interleukin – 1 and atherosclerosis exists. Interleukin – 1 increases endothelial adhesion molecules, as well as cytokine and chemokine expression, and thereby helps with the recruitment of leukocytes. 49 The interleukin – 1 family consists of 11 cytokines. They are expressed by all cells of the innate immune system. Auto-inflammatory and auto-immune diseases, as well as degenerative and infectious diseases, all are strongly driven by interleukin – 1 communication. Interleukin – 1 has an effect on the hypothalamus– pituary–adrenal axis (resulting in fever and increased cortisol release), the acute- phase response in the liver (mediated via interleukin – 6), induction of endothelial adhesion molecules, and the lifespan of neutrophils and macrophages. In addition, interleukin – 1 has self-promoting properties, amplifying its own release. 50 The three most-studied members of the family are interleukin – 1 α , interleukin – 1 β , and interleukin – 1 receptor antagonist. These three cytokines compete in binding to the interleukin – 1 receptor. 51 The interleukin – 1 α precursor is present in epithelial cells and is released after cell death. It is fully active, acting in the early response in sterile inflammation. 52 The membrane form of active interleukin – 1 α is found in activated monocytes. 50,53 Interleukin – 1 β is the main form of circulating interleukin – 1 and it is produced by hematopoietic cells, such as monocytes/macrophages. The precursor of interleukin – 1 β is not active until cleaved by caspase 1, after which the active cytokine will be released in the extracellular compartment. Although interleukin – 1 α and interleukin – 1 β differ in source and releasemechanism, both bind to the interleukin – 1 receptor and thus initiate similar inflammatory cascades. 51