Negative Regulation of Inflammation by Fas Ligand Expression on the Vascular Endothelium

Abstract

It is generally believed that the vascular endothelium serves as a barrier to inflammation by providing a nonadherent surface to leukocytes. Recently, we reported that vascular endothelial cells (ECs) express Fas ligand, which functions to actively inhibit inflammation by inducing apoptosis in Fas-bearing leukocytes. The inflammatory cytokine TNFα downregulates Fas ligand expression with an accompanying decrease in EC cytotoxicity toward Fas-bearing cells in co-culture. Endothelial Fas ligand expression in arteries is also downregulated by the local administration of TNFα, and this correlates with robust mononuclear cell infiltration of the subendothelial space. This TNFα-induced mononuclear cell infiltration is inhibited by pre-infecting the endothelium with a replication-defective adenovirus that constitutively expresses Fas ligand. Under these conditions, adherent leukocytes undergo apoptosis rather than extravasation. These findings suggest that Fas ligand expression on the vascular endothelium functions to inhibit inflammatory responses that are often associated with vascular disorders.