Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3)

Decoy receptor 3 (DcR3) is a soluble decoy receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily, and its expression is not only up-regulated in cancer cells derived from various cell lineages, but also correlates with overall survival of patients with cancer. It has been shown that DcR3 sensitize cells of hematopoietic origin to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis; therefore, we asked whether DcR3 down-regulated host immunity by inducing immune cell apoptosis. We demonstrate that DcR3 induces dendritic cell (DC) apoptosis by activating PKC-delta and JNK subsequently to up-regulate DR5 to recruit Fas-associated death domain (FADD) to propagate the apoptotic signals. The association of FADD with DR5 results in the formation of death-inducing signaling complex (DISC) to trigger the downstream apoptotic signaling cascade. PKC-delta is activated via cross-linking of heparan sulfate proteoglycan (HSPG) on DCs, because recombinant protein containing the heparin-binding domain (HBD) of DcR3 and the Fc portion of IgG(1), the HBD.Fc fusion protein, is also able to trigger DC apoptosis. This provides the first evidence that cross-linking of HSPG on DCs can activate PKC-delta to induce DC apoptosis via the formation of DR5 DISC, and elucidates a novel mechanism of DcR3-mediated immunosuppression.