Interleukin 16 in Atherosclerosis and Cardiovascular Disease

Background and aim The development of clinical manifictations due to an eroded or ruptured atherosclerotic plaque, or occluded vessel, are one of the major causes of death world wide. It has been known for some time that atherosclerosis develops due to retention and modification of LDL particles in the vessel wall and the subsequent triggering of the immune system. The research presented within this thesis has focused on IL-16, a signaling molecule, in the immune system. IL-16 has shown pleiotropic functions in inflammatory diseases. IL-16 has been described to have the capacity to induce T cell unresponsivness and increase the regulatory T cell population. Regulatory T cells are known to be protective in atherosclerosis by dampening the immune responses. There has been no extensive research on the role of IL-16 in atherosclerosis disease and the clinical manifestations thereof. The aim of the collected work in this thesis was to investigate if IL-16 can induce antiinflammatory and atherosclerosis dampening effects, if IL-16 holds potential as a biomarker for prediciting future cardiovascular events, and if IL-16 is altered in an retrospective cardiovascular case-control study. Results – (I) Administration of IL-16, in an experimental model of atherosclerosis consisting of hypercholesterolemic female mice, increased anti-inflammatory factors and decreased the atherosclerotic plaque burden. Male mice, which were defective of IL-16, displayed an increased atherosclerotic burden compared to control mice. (II) Elevated levels of IL-16, in carotid plaques, from individuals with severe carotid atherosclerosis displayed associations to plaque stabilizing components (collagen, elastin and FoxP3). High levels of carotid plaque IL-16 were associated to a decreased risk of suffering from a cardiovascular event. (III) Individuals suffering from severe carotid atherosclerosis had a decreased risk of suffering from a post-operative cardiovascular event, or a cardiovascular event leading to death, if they had high levels of circulating IL-16 compared to individuals with low levels of IL-16. (IV) In a population-based prospective study four single nucleotide polymophisms (SNPs) were found to be associated with IL-16 plasma levels. High plasma levels of IL16 were associated with an increased risk of myocaridal infarction in women, compared to women with low levels of circulating IL-16. None of the SNPs were associated with an increased risk of cardiovascular events. One of the identified SNPs was associated with a decreased risk of all-cause mortality during the 20-year follow-up period. (V) In a retrospective case-control study, including individuals suffering from diabetes, IL-16 was 50% elevated in individuals whom also suffered from cardiovascular complications compared to the individuals only suffering from diabetes. Plasma levels of IL-16 were associated with surrogate markers of atherosclerosis which was further supported by SNP analysis. Conclusion IL-16 in plasma did not display associtions to a decreased risk of cardiovascular events in a prospective population-based study, rather the opposite. We have presented supporting evidence of a protective role of IL-16 in severe and experimental atherosclerosis, reinforced by the associations between high IL-16 levles and increasing amounts of stabilizing factors in the atherosclerotic plaque. We also present supporting evidence, in an experimental setting, for an anti-inflammatory role and plaque burden limiting role of IL-16. The data presented within this thesis warrents futher investigation of the plaque stabilizing properties of IL-16 in severe atherosclerosis and the role of IL-16 in promoting anti-inflammatory mediators.