Study on the mechanism of atherosclerotic lesion formation using cytokine-knockout mouse

1.在TNF-α^<-/-> apoE^<-/->双基因敲除小鼠与apoE^<-/->敲除小鼠的比较研究中，双基因敲除小鼠的动脉粥样硬化病变面积明显减小。此外，双基因敲除小鼠细胞间粘附分子ICAM-1、VCAM-1的表达也明显受到抑制。2. IFN-γ^<-/-> apoE^<-/->双基因敲除小鼠的动脉粥样硬化病变较apoE ^<-/->敲除小鼠明显减轻，ICAM-1和VCAM-1的mRNA水平明显降低。提示IL-1β可募集单核细胞（包括单核细胞）至动脉壁，导致动脉粥样硬化病变的形成。3. IFN-γ^<-/->BMT小鼠的动脉粥样硬化病变在主动脉窦、主动脉弓和腹主动脉处均大于IFN-γ^<+/+>BMT小鼠。这些结果表明，骨髓源性细胞产生的IFN-γ可以延缓动脉粥样硬化的进展，而对血脂没有任何影响，这种抑制作用可能是由于减少了细胞外基质的沉积。然而，来自骨髓的IFN-γ至少在初始阶段相当抑制动脉粥样硬化。

1.In the study on the comparison of TNF-α^<-/-> apoE^<-/-> double KO mouse with apoE^<-/-> KO mice, the area of atherosclerotic lesion was significantly reduced in double KO mice. In addition, the expression of adhesion molecules such as ICAM-1and VCAM-1was also significantly suppressed in double KO mouse. These fidings suggest that augumented expression of adhesion molecules is, at least in part, involved in the atherosclerotic action of TNF-α.2.The atherosclerotic lesion was significantly reduced in IFN-γ^<-/-> apoE^<-/-> double KO mice compared with apoE^<-/-> KO mice and mRNA levels of ICAM-1 and VCAM-1 were significantly decreased in double KO mice. It is suggested that mononuclear cells including monocytes are recruited to arterial wall by IL-1β, resulting in the formation of atherosclerotic lesion.3.The atherosclerotic lesions of IFN-γ^<-/->BMT mice were larger than those of IFN-γ^<+/+>BMT mice at the aortic sinus, aortic arch and abdominal aorta. These findings show that IFN-γ produced by bone marrow-derived cells delays the progression of atherosclerosis without any effects on plasma lipids, and this suppression may be due to decreased extracellular matrix deposition.In this study, we clarified that TNF-α and IL-1β accelerate atherosclerosis via the augumented expression of adhesion molecules in vivo study. However, IFN-y derived from bone marrow rather suppressed atherosclerosis at least in the initial stage.