The Relationship Between Interleukin-18 And Diabetic Macrovascular Complication

Patients with type 2 diabetes have a high incidence of atherosclerosis,which leads to increased mortality from coronary disease(CAD),cerebrovascular disease and peripheral vascular disease(PVD).At the bases of the atherogensis there are complex interactions between macrophages, T lymphocytes and smooth muscle cells.Inflammatory mechanisims play a pivotal role in the atherosclerotic process, especially in atherosclerotic plaque growth and in plaque instability. Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids, cells(macrophages, T lymphocytes, and smooth muscle cells[SMCs]), and extracellular matrix. A large body of evidence suggests that the inflammatory process plays a major role throughout the development of the atherosclerotic lesion. Inflammation is also involved in atherosclerotic plaque disruption and thrombosis and may greatly influence the occurrence of acute ischemic syndromes and their related mortality. Plasma concentrations of several inflammatory markers such as C-reactive protein(CRP) and interleukin(IL)-6 have been lined with future cardiovascular disease.Interleukin(IL)-18,initially described as an endotoxin-induced serum factor that stimulates IFN-γ production,IL-18 and IL-12 act synergistically to induce the production of IFN-γ in T cells, natural killer cells, and subsets of macrophages might be involved in atherosclerosis. IL-18 is a proinflammatory cytokine produced mainlyby monocytes/macrophages, with potent activities on both macrophages and T cells, two cell types involved in the development and complications of human atherosclerotic plaques. IL-18 shows the most potent synergism with IL-12 for the induction of IFN-y.These latter cytokines are expressed in atherosclerotic plaques and have been implicated in the immunoinflammatory response that determines both the size and the composition of the atherosclerotic lesion in animal models of atherosclerosis. IFN-y greatly affects collagen content of atherosclerotic plaque, in part through inhibition of collagen synthesis by SMCs. As a result, IFN-yis thought to participate in plaque destabilized by preventing the formation of a thick fibrous cap. Therefore/we hypothesized that the IFN-y-inducing factor,IL-18,may be involved in atherosclerosis progression.Recently increased expression of IL-18 has been reported in caroud ulcerated atherosclerotic plaques,suggesting that IL-18 also play a role in plaque destabilization.Interleukin-18 binding protein(IL-18BP)is a novel glycoprotein and belongs to the immunoglobulin superfamily so far, four human and two mouse IL-18BP isoforums have been found in various cDNA libraries. IL-18BP is regarded as a nature antagonist for IL-18 which efficiently inhibits the biological functions of IL-18 in vitro and in vivo.Blankenberg pointed out that IL-18 played a central role in accelerating atherosclerosis and plaque vulnerability in animal models.He said that serum IL-18 level was identified as a strong independent predictor of death from cardiovascular causes in patients with coronary artery disease regardless of the clinical status at admission. This result strongly supports recent experimental evidence of IL-18-mediated inflammation leading to acceleration and vulnerability of atherosclerotic plaques.Methods: 68 case with type 2 diabetes in which 48 patients suffered from macrovascular complications (MVC) and 20 did not, compared with the normal controls(NC). Interleukin-18 were measured using a commercially available enzyme-linked immunosorbent assay (ABC-ELISA),and others markers related to macrovascular complications were also measured. Carotid Intimal-Media Wall Thickness (IMT) of the common carotid artery was determined using duplexultrasonography to know the degree of atherosclerosis. To define the independent association between Serum Interleukin-18 and diabetic macrovascular complications, the multiple stepwise logstic regressive analysis was used.Results: 1. The results suggest that serum interleukin-18 level was higher in type 2-diabetes group than that in the control. Serum Interleukin-18 level was in diabetic macrovascular complications group which was higher than in the non-diabetic macrovascular complications group and in the normal controls (F=32.975 , P<0.01 ) ,and carotid IMT is higher in patients with higher interleukin-18.2. The multiple stepwise regressive analysis was used to define carotid IMT and other factors, interleukin-18, age, HOMA-IR, and diastole blood pressure correlated carotid IMT significant at F=\ 1.88^=0.000.3. To define the independent association between serum interleukin-18 and diabetic macrovascular complications, the multiple stepwise logstic regressive analysis was used. Serum Interleukin-18 but not other parameters related independently and significantly with macrovascular complications, so did age, duration, and triglyceride.Conclusion: The study suggests that Interleukin-18 may an important independent risk factor for diabetic macrovascular complications.