Jf. Mchale et al., TNF-alpha and IL-1 sequentially induce endothelial ICAM-1 and VCAM-1 expression in MRL/lpr lupus-prone mice, J IMMUNOL, 163(7), 1999, pp. 3993-4000
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.