McHale J F, Harari O A, Marshall D, Haskard D O
British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
J Immunol. 1999 Oct 1;163(7):3993-4000.
Dysfunctional leukocyte-endothelial interactions are thought to play a key role in systemic lupus erythematosus pathogenesis. We questioned the importance of TNF-alpha and IL-1 for endothelial activation in MRL/lpr lupus-prone mice. Endothelial ICAM-1 and VCAM-1 expression increased significantly with disease evolution in kidney, heart, and brain, as shown by i.v. injected radiolabeled Ab uptake. Lung endothelial VCAM-1 also increased, while lung endothelial ICAM-1 did not rise above a high basal level. Immunoassays showed a significantly raised circulating level of TNF-alpha by 14 wk, with levels of circulating IL-1alpha and IL-1beta being additionally raised by 20 wk. With 14-wk-old MRL/lpr, anti-TNF-alpha antiserum inhibited expression of ICAM-1 and VCAM-1 by endothelial cells cultured with sera in vitro, and uptake of anti-ICAM-1 and anti-VCAM-1 mAb in lung, kidney, brain, and heart in vivo. In contrast, both anti-TNF-alpha and anti-IL-1 antisera were required for maximal inhibition in vitro and in vivo at 20 wk. These data indicate that TNF-alpha is largely responsible for the early up-regulation of endothelial ICAM-1 and VCAM-1, but that IL-1 enhances expression in late disease. Our observations provide novel insights of possible relevance to understanding endothelial activation in systemic lupus erythematosus, and highlight an approach that can be extended to dissecting other chronic inflammatory diseases.
功能失调的白细胞-内皮细胞相互作用被认为在系统性红斑狼疮发病机制中起关键作用。我们质疑肿瘤坏死因子-α（TNF-α）和白细胞介素-1（IL-1）对MRL/lpr狼疮易感小鼠内皮细胞活化的重要性。静脉注射放射性标记抗体摄取显示，随着疾病在肾脏、心脏和大脑中的进展，内皮细胞细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）表达显著增加。肺内皮细胞VCAM-1也增加，而肺内皮细胞ICAM-1未升高至高于高基础水平。免疫测定显示，到14周时循环中TNF-α水平显著升高，到20周时循环中IL-1α和IL-1β水平进一步升高。对于14周龄的MRL/lpr小鼠，抗TNF-α抗血清在体外抑制用血清培养的内皮细胞ICAM-1和VCAM-1的表达，并在体内抑制肺、肾、脑和心脏中抗ICAM-1和抗VCAM-1单克隆抗体的摄取。相比之下，在20周时，体外和体内最大抑制作用都需要抗TNF-α和抗IL-1抗血清。这些数据表明，TNF-α在很大程度上负责内皮细胞ICAM-1和VCAM-1的早期上调，但IL-1在疾病后期增强表达。我们的观察结果为理解系统性红斑狼疮中的内皮细胞活化提供了可能相关的新见解，并突出了一种可扩展到剖析其他慢性炎症性疾病的方法。
