.trail / Trail Receptor-mediated Inflammatory Response And Its Signaling Pathway

Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL),which is also designated as Apo-2 ligand,is a typical member of the structurally related TNF family.To date five TRAIL receptors have been identified in human:TRAIL-R1(DR4),TRAIL-R2 (DR5),TRAIL-R3(DcR1,TRID),TRAIL-R4(DcR2,TRUNDD) and OPG (osteoprotegerin).Among these receptors,DR4 and DR5 possess an intracellular tail containing the death domain,which mediated cell death by apoptosis.In contrast,DcR2 possesses a truncated death domain and DcR1 have no death domain.Osteoprotegerin is a soluble TRAIL receptor,which is known to participate in regulation of bone density.TRAIL has been known to induce apoptosis in a variety of tumor cells and some vitally infected cells,but not in most normal cells.Thus TRAIL and TRAIL death receptor specific agonistic antibodies have attracted considerable attention for their potential use in cancer therapy.TRAIL receptor overexpression as well as TRAIL treatment induced apoptosis in different cell lines.Once engaged,TRAIL receptors recruit a number of adaptor proteins and subsequently a signaling cascade is activated.Most investigations about TRAIL focused on its ability to induce apoptosis in cancer cells;however,the physiological function of TRAIL and TRAIL receptors is much less well understood.Compared with other members of TNF superfamily,TRAIL are widely expressed in the immune system,including activated T cells,B cells,natural killer cells, dendritic cells,neutrophils,and monocytes.DR4 and DR5 are detected in most human tissues,such as spleen,peripheral blood leukocytes,and thymus.Although TRAIL and its receptors are both expressed in many normal cells,TRAIL seldom initiates apoptosis in these cells.The fact suggests that the physiological roles of TRAIL and TRAIL receptors are more complex than just inducing apoptosis of cancer cells.In order to shed a light on the physiological roles of TRAIL receptors,we transfected 293T cells with expression plasmids of DR4 or DR5 to determine whether TRAIL receptors overexpression activated inflammatory cytokines release.To our knowledge,this is the first demonstration that TRAIL receptors overexpression activates inflammatory cytokine release in a NF-κB dependent signaling pathway.We described that DR4 and DR5-mediated inflammation and apoptosis was extra cellular domain independent. Furthermore,TRAF2-NIK-IKKα/βsignaling cascade,which plays an essential role in TNF-induced NF-κB activation,is involved in TRAIL receptors overexpression-activated signaling pathway.And FADD-Caspases signaling pathway,which was reported to be mostly related to apoptosis,was elucidated to be essential for TRAIL receptors-mediated inflammation.To present further evidence,we treated 293T and HCT-116 cells with rsTRAIL to determine whether TRAIL induced inflammatory cytokines release.We elucidated that TRAIL induced IL-8,CCL20,MIP-2,MIP-1βand MCP-1 secretion in a NF-κB dependent manner.RIP was proved to be essential for TRAIL-induced chemokines release,while TRADD and TRAF2 were not required.It was also demonstrated that p38 MAPK was involved in TRAIL-induced chemokines release without any effect on NF-κB activity, which suggested that some other transcription factors were also activated by TRAIL. Furthermore,using xenografi tumor model,we illustrated that TRAIL induced chemokines release in vivo.These data provide novel evidences for the physiological functions of TRAIL and TRAIL receptor,and throw some light on their clinical application.