IFN gamma and its transcriptional target tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) are two major effector molecules of activated CTLs and NK cells. Here, we show that IFN gamma as well as the type I interferon IFN alpha strongly inhibit cell surface expression of the decoy receptor TRAILR4 while having only a moderate inhibitory or even an inducing effect on TRAILR2 and CD95. Interferon-induced inhibition of TRAILR4 expression was blocked by a protease inhibitor cocktail and also by MG132, suggesting that down-regulation of TRAILR4 involves the proteasome. Inhibition of TRAILR4 expression by siRNA sensitized for TRAIL-, but not CD95L-induced apoptosis. Thus, the apoptosis-inducing action of interferons may not only rely on the well-established induction of TRAIL in effector cells but also on concomitant down-regulation of its antagonizing decoy receptor TRAILR4 in target cells. (c) 2005 Elsevier Inc. All rights reserved.