[8-12] Studies in vivo have also demonstrated a role in colitis and ileitis.[13-17] DR3 regulates immunity to certain bacteria,[18] viruses,[19] tumours[20] and intrinsically maintains NVP-BGJ398 order neurological function.[21] Research in humans has mirrored these findings, primarily showing that DR3 regulates

inflammation and immunity through controlling the development of effector T cells and differentiation of myeloid subsets,[22-30] but it may also have effects on other cell types such as neurons.[31] Local and systemic increases of its ligand are associated with multiple human inflammatory disorders.[32-35] In this respect, the designation ‘Death Receptor 3’ is a misnomer because many of the recognized functions of the gene are associated with cell expansion and differentiation, rather than death. Park et al.[1] clearly describe an increase in cell viability of tumour cell lines following exposure to natural killer (NK) cells when DR3 expression was knocked down; results consistent with DR3 acting to trigger cell death.

To my knowledge, this is the first functional demonstration of a pro-apoptotic role for DR3 in human tumour cell lines, but it is not unique as a general phenomenon. The original DR3 knockout mouse exhibited a defect in negative selection of thymocytes,[36] while DR3-dependent apoptosis Vildagliptin has been described in renal inflammation in vivo[37] and osteoblast cell lines in vitro.[38] Furthermore, a role in human cancer has been implied from the discovery that this website the DR3 gene is disrupted in ~ 40% of neuroblastomas.[39] It is in this context that clarification is useful on the nature of the DR3 ligand, as its identity is also complicated by a history of diverse nomenclature. Park et al.[1] mention two ligands in their references, Apo3L and TL1A, both of which are distinct tumour necrosis factor superfamily (TNFSF) members. Apo3L was originally named as the ligand for DR3 (i.e. Apo3)[40] and was also called TWEAK (TNFSF12). However,

follow-up studies could not confirm this[41] and indicated that TWEAK signalled in the absence of DR3.[42] A second receptor for TWEAK, Fn14 (TNFRSF12A), was then identified,[43] and TL1A (TNFSF15 and the full-length gene product of the vascular endothelial growth inhibitor, VEGI) was found to bind DR3.[44] All-encompassing work from Bossen et al.[45] involving flow cytometric binding assays between the majority of human and murine TNFSF:Fc proteins and cell lines transfected with TNFRSF members confirmed this, i.e. that TWEAK binds Fn14, whereas TL1A binds DR3 and there is minimal cross-reactivity, findings that have been borne out in later in vivo experiments using gene knockouts.