The tumor necrosis factor-related apoptosis-inducing ligand receptors TRAIL-R1 and TRAIL-R2 have distinct cross-linking requirements for initiation of apoptosis and are non-redundant in JNK activation

Overexpression of the tumor necrosis factor (TNF)related apoptosis-inducing ligand (TRAIL) receptors, TRAIL-Ri and TRAIL-R2, induces apoptosis and act ivation of NF-kappa B in cultured cells. In this study, we have demonstrate d differential signaling capacities by both receptors using either epitope- tagged soluble TRAIL (sTRAIL) or sTRAIL that was cross-linked with a monocl onal antibody. Interestingly, sTRAIL was sufficient for induction of apopto sis only in cell lines that were killed by agonistic TRAIL-R1- and TRAIL-R2 -specific IgG preparations. Moreover, in these cell lines interleukin-6 sec retion and NF-kappa B activation were induced by crosslinked or non-cross-l inked anti-TRAIL, as well as by both receptor-specific IgGs. However, cross -linking of sTRAIL was required for induction of apoptosis in cell lines th at only responded to the agonistic anti-TRAIL-R2-IgG. Interestingly, activa tion of c-Jun N-terminal kinase (JNK) was only observed in response to eith er cross-linked sTRAIL or anti-TRAIL-R2-IgG even in cell lines where both r eceptors were capable of signaling apoptosis and MF-kappa B activation. Tak en together, our data suggest that TRAIL-R1 responds to either cross-linked or non-cross-linked sTRAIL which signals NF-kappa B activation and apoptos is, whereas TRAIL-R2 signals NF-kappa B activation, apoptosis, and JNK acti vation only in response to crosslinked TRAIL.