Rel/NF-kappa B transcription factors protect against tumor necrosis factor(TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcR1

Rel/nuclear factor (NF)-kappaB transcription factors play a major role in t he regulation of programmed cell death. A few anti-apoptotic Rel/NF-kappaB target genes have been characterized; they act either downstream in the apo ptotic pathway or upstream, for example at the tumor necrosis factor (TNF) receptor Level. We found using DNA arrays, reverse transcription-polymerase chain reaction, and immunofluorescence that Rel/NF-kappaB factors up-regul ate DcR1, a receptor for TNF-related apoptosis-inducing ligand (TRAIL), a c ytokine of the TNF family that induces apoptosis in tumor cells. Four relat ed receptors bind TRAIL, two death receptors (DR4 and DR5) that signal apop tosis and two decoy receptors (DcR1 and DcR2) that act as dominant negative inhibitors of TRAIL-mediated apoptosis. DcR1 is devoid of an intracellular domain and is anchored at the cell surface membrane by a glycophospholipid . Our results indicate that overexpression of cRel or activation of endogen ous Rel/NF-kappaB factors by TNF alpha in HeLa cells up-regulates DcR1 with out changing the expression of DcR2, DR4, and DR5 and makes cells resistant against TRAIL-induced apoptosis. This resistance is a consequence of DcR1 upregulation,,because it was abolished when DcR1 was removed from the cell surface by a phosphatidylinositol phospholipase C. Therefore, Rel/NF-kappaB transcription factors could regulate the sensitivity of cells to TRAIL, by : controlling the ratio of TRAIL-decoy to -death receptors.