CommentaryDecoy receptor 3: A pleiotropic immunomodulator and biomarker for inflammatory diseases, autoimmune diseases and cancer
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Discovery and characterisation of DcR3 gene and protein
Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor (TNFR) superfamily member 6b (TNFRSF6B)/TR6/M68, is a soluble receptor lacking a transmembrane domain and capable of neutralizing the biological effects of three members of the tumor necrosis factor superfamily (TNFSF): Fas ligand (FasL/CD95L/TNFSF6) [1], LIGHT [lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus (HSV) glycoprotein D (gD) for HVEM, a receptor expressed by T
Decoy functions of DcR3 to cytokine ligands
Initial understanding of DcR3-mediated functions was derived from its interactions with three members of the TNFSF, i.e. FasL, LIGHT, and TL1A (Fig. 1), where the activities of DcR3 were hypothesized on the basis of the biological functions of these ligands. Recent review articles have discussed FasL [9], LIGHT [10], [11], and TL1A [12], [13] in detail; here we briefly summarize key features of FasL, LIGHT and TL1A before reviewing their relevance to DcR3 function. In particular, we focus on
Non-decoy actions of DcR3
In addition to neutralizing TL1A, LIGHT and FasL, DcR3 also acts as an effector molecule to modulate the activities of many cell types directly (Fig. 2).
DcR3 as a biomarker in cancer progression
There is accumulating evidence that DcR3 is expressed by tumor cells originating from various lineages, including adenocarcinomas of the esophagus [54], stomach [55], colon, rectum [1], pancreas [56], lung [1], glioblastoma multiforme [36], [57], renal cell cancer (RCC) [58], ovarian cancer [59], virus-associated lymphomas [60], diffuse large B-cell lymphoma [61], multiple myeloma [62], oral cancer [63], hepatocellular carcinoma [64], and chronic liver diseases, which frequently lead to cancer
DcR3 as a biomarker for autoimmune and inflammatory diseases
DcR3 is not detectable in most normal tissues, but its expression is upregulated in response to some pathogens or insults. In particular DcR3 levels are elevated in systemic inflammatory diseases, where serum concentrations are significantly increased in silicosis [74], bacterial infections [75], Crohn's disease [76], active ulcerative colitis [31], systemic lupus erythematosus [77], atopic dermatitis [78], experimental autoimmune encephalomyelitis (EAE) [79], RA [32], kidney diseases [80] and
Upregulation of DcR3 by Epstein–Barr virus
Although DcR3 expression is known to be upregulated in cancer cells, its regulation is not well understood. It has been reported that DcR3 is overexpressed in Epstein–Barr virus (EBV)-associated lymphoma, but not in reactive lymphadenopathy [60]. This suggests that EBV might use DcR3 to evade the immune system during lymphomagenesis, or that virus-infected lymphoma cells expressing DcR3 might be selected during multistep tumorigenesis. In this regard, the EBV transcription activator Rta has
Type 1 diabetes
Given that type I diabetes is a Th1-mediated autoimmune disease, DcR3-mediated Th1 suppression becomes a new strategy for this condition. In vivo and in vitro studies support the notion that DC-derived Th1 activity contributes to disease progression, where DcR3 might limit this by modulating DC differentiation [91], [92]. DcR3.Fc treatment of bone-marrow-derived DCs from nonobese diabetic (NOD) mice, the prototype animal model of type I diabetes, leads to upregulation of CD86 and downregulation
Conclusions and perspectives
DcR3 is a novel immunosuppressant whose biological functions result in part from its ability to neutralize the activities of TL1A, LIGHT and FasL, as well as from non-decoy functions. Since soluble DcR3 levels will likely affect the homeostasis of cells and tissues, understanding the regulation of DcR3 expression in specific pathophysiological conditions might provide important insights into disease progression and treatment.
The overexpression of DcR3 protein might provide an important
Acknowledgements
The authors greatly acknowledge Miss Hsin-Chuan Chang for technical assistance, and the financial support of the National Research Program for Genomic Medicine, National Science Council, Taiwan (NSC 99-2811-B-010-018, NSC 99-3112-B-010-011, NSC98-2320-B-002-010-MY3 and NSC 98-2320-B-010-022-MY3), the National Yang-Ming University, Taiwan (96A-D-D132 from MOE), and Taipei Veterans General Hospital (V97S5-001).
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