Atherogenic effect of interleukin-2 and antiatherogenic effect of interleukin-2 antibody in apo-E-deficient mice

Growing evidence suggests that atherosclerosis is an immune-mediated inflammatory process and that cytokines participate as mediators in this process. Of the cytokines, interleukins, which are released from both immune and nonimmune cells of vascular wall, are found to have multiple effects. Interleukin-2 (IL-2), a cytokine produced by activated T-lymphocytes, has been found to further activate the T cells and may potentially enhance atherogenesis. Apo-E-deficient mice fed with atherogenic diet were injected intraperitoneally twice a week with placebo, IL-2, or anti-IL-2 antibody for a period of 6 weeks. Group 1 (n = 6) was injected with bovine serum albumin (BSA) in phosphate-buffered saline (PBS) and served as controls. Group 2 (n=6) was injected with 2 x 10(4) units of recombinant murine IL-2 (rmIL-2) per dose reconstituted with BSA in PBS. Group 3 (n=6) was injected with 5 microg of anti-IL-2 per dose reconstituted with BSA in PBS. Aortic sections were analyzed and atherosclerotic burden was quantified. Compared to controls, injection of IL-2 increased measures of atherosclerosis such as the average lesion score (10.7 +/-0.5 vs 9.3 +/-1.1, p=0.04) and the lesion size as a fraction of aortic area (0.51 +/-0.03 vs 0.41 +/-0.05, p=0.01). Injection of anti-IL-2 had a profound antiatherogenic effect. It significantly reduced the average number of lesions per cross section (2.6 +/-0.6 vs 4.3 +/-0.6, p=0.03), the average lesion score (4.6 +/-1.9 vs 9.3 +/-1.1, p=0.02), the lesion area/circumference (0.35 +/-0.08 vs 0.62 +/-0.10, p=0.007), and the lesion size/aortic area (0.23 +/-0.07 vs 0.41 +/-0.05, p=0.03). These results indicate that IL-2 is an atherogenic cytokine in apo-E-deficient mice and anti-IL-2 is protective against atherosclerosis. This may have important clinical implications in modifying the atherosclerotic process.