TNF-alpha and IL-1 sequentially induce endothelial ICAM-1 and VCAM-1 expression in MRL/lpr lupus-prone mice

Dysfunctional leukocyte endothelial interactions are thought to play a key role in systemic lupus erythematosus pathogenesis. We questioned the import ance of TNF-alpha and IL-1 for endothelial activation in MRL/lpr lupus-pron e mice. Endothelial ICAM-1 and VCAM-1 expression increased significantly wi th 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 sho wed a significantly raised circulating level of TNF-alpha by 14 wk, with le vels of circulating IL-1 alpha and IL-1 beta being additionally raised by 2 0 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 hear t in vivo. In contrast, both anti-TNF-alpha and anti-IL-1 antisera were req uired for maximal inhibition in vitro and in vivo at 20 wk. These data indi cate that TNF-alpha is largely responsible for the early up-regulation of e ndothelial ICAM-1 and VCAM-1, but that IL-1 enhances expression in late dis ease. Our observations provide novel insights of possible relevance to unde rstanding endothelial activation in systemic lupus erythematosus, and highl ight an approach that can be extended to dissecting other chronic inflammat ory diseases.