Abstract 519: Pathogenic Mechanisms of Il-17 In Atherogenesis - In Vivo and In Vitro Studies
Atherosclerotic plaque typically contains infiltrates of activated macrophages and T cells. In human carotid artery plaques, we previously showed the presence of IL-17 producing T cells (Th17) and IL-23. This study investigated possible pathogenic mechanisms of IL-17 on atherogenesis in ApoE−/− mice and its effects on vascular cells in vitro. 25 female ApoE−/− mice fed a normal diet were treated with a specific blocking antibody against IL-17 for 12 weeks (100 μg intraperitoneally once per week) compared to unteated mice (reveiving a control IgG). In vitro endothelial cells and RAW cells were either treated with IL-17 1000ng/ml alone as well as in addition to TNF-α or LPS. SMCs were incubated with IL-17 or additional IFN-γ to induce apoptosis. IL-17 mAb treatment resulted in a > 60% reduction of plaque volume and fractional luminal stenosis in the aortic root. IL-17 mAb treated mice showed higher percentage of collagen content in the lesion, especially in the area of the fibrous cap. In addition, the amount of SMCs was also significantly higher in the area of the fibrous cap in IL-17 mAb treated mice. RT-PCR results showed signifcantly reduced caspase 3 expression in IL-17 mAb treated mice. The possible stabilizing effects in IL-17 mAb treated mice was in line with findings that IL-17 was found to induce apoptosis in SMCs in vitro. In vitro studies further showed that IL-17 itself induced pro-inflammatory changes in macrophages as well as endothelial cells and also acted synergistically with TNF-α or LPS. Functional blockade of Th1 cytokine IL-17 reduces atherosclerotic plaque, stabilizes the atherosclerotic lesion by higher amount of SMC and collagen content in the area of the fibrous cap as well as reduced apoptosis in the lesion. Inflammatory changes in ECs, Ms and SMCs leading to cell death and increased immune cell infiltration may represent possible pathogenic mechanisms of IL-17 in atherogenesis.