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Endothelial Fas ligand (FasL) contributes to the "immune privilege" of tissues such as testis and eye, in which apoptosis is induced in infiltrating Fas-positive activated T cells and results in the inhibition of leukocyte extravasation. In this study, we examined the role of endothelial FasL in controlling cancer cell transmigration using rat lung endothelial (RLE) cell line bearing a doxycycline-inducible hepatocyte nuclear factor (HNF)-4alpha expression system. We showed that a detectable level of FasL was expressed in RLE cells and that this expression was markedly up-regulated and well correlated to the degree of HNF-4alpha expression in a time-dependent manner. When various cancer cells were overlaid on an RLE monolayer sheet, we examined the ability of endothelial FasL to induce massive apoptosis in Fas-expressing cancer cells and found a causal link to inhibition of the transmigration. Finally, we showed that FasL was expressed in capillaries of the rat brain by immunohistochemical staining, suggesting that FasL serves its functions not only in vitro, but also in vivo. These results raise the possibility that HNF-4alpha is involved in regulating cancer cell transmigration by modulating the Fas-FasL system.