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

1.在肿瘤坏死因子-α；-/-&gt；-/-&gt；双KO小鼠与apoE^&lt；-/-&gt；KO小鼠的比较研究中，双KO小鼠动脉粥样硬化病变面积明显缩小。此外，ICAM-1和VCAM-1等黏附分子在双KO小鼠体内的表达也受到明显抑制。这些结果提示，黏附分子的表达增强至少部分参与了肿瘤坏死因子-α的动脉粥样硬化作用。2.与载脂蛋白E^&lt；-/-&gt；-/-&gt；双重γ小鼠相比，双重ko小鼠的动脉粥样硬化病变明显减轻，细胞间黏附分子-1和血管细胞间黏附分子-1的表达水平显著降低。提示IL-1β可将包括单核细胞在内的单个核细胞聚集到动脉壁上，导致动脉粥样硬化病变的形成。3.在主动脉窦、主动脉弓和腹主动脉，干扰素-γ；-/-&gt；BMT小鼠的动脉粥样硬化病变比干扰素-γ^-+&gt；这些结果表明，骨髓源性细胞产生的干扰素-γ在不影响血脂的情况下延缓了动脉粥样硬化的进展，这种抑制可能是由于减少了细胞外基质的沉积。在本研究中，我们阐明了肿瘤坏死因子-α和IL-1β通过促进体内黏附分子的表达来加速动脉粥样硬化。然而，骨髓来源的干扰素-γ至少在早期阶段对动脉粥样硬化有一定的抑制作用。

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.