Abstract
Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor (TNFR) superfamily member 6b (TNFRSF6B), is a soluble decoy receptor which can neutralize the biological functions of three members of tumor necrosis factor superfamily (TNFSF): Fas ligand (FasL), LIGHT, and TL1A. In addition to ‘decoy’ function, recombinant DcR3.Fc is able to modulate the activation and differentiation of dendritic cells (DCs) and macrophages via ‘non-decoy’ action. DcR3-treated DCs skew T cell differentiation into Th2 phenotype, while DcR3-treated macrophages behave M2 phenotype. DcR3 is upregulated in various cancer cells and several inflammatory tissues, and is regarded as a potential biomarker to predict inflammatory disease progression and cancer metastasis. However, whether DcR3 is a pathogenic factor or a suppressor to attenuate inflammatory reactions, has not been discussed comprehensively yet. Because mouse genome does not have DcR3, it is not feasible to investigate its physiological functions by gene-knockout approach. However, DcR3-mediated effects in vitro are determined via overexpressing DcR3 or addition of recombinant DcR3.Fc fusion protein. Moreover, CD68-driven DcR3 transgenic mice are used to investigate DcR3-mediated systemic effects in vivo. Upregulation of DcR3 during inflammatory reactions exerts negative-feedback to suppress inflammation, while tumor cells hijack DcR3 to prevent apoptosis and promote tumor growth and invasion. Thus, ‘switch-on’ of DcR3 expression may be feasible for the treatment of inflammatory diseases and enhance tissue repairing, while ‘switch-off’ of DcR3 expression can enhance tumor apoptosis and suppress tumor growth in vivo.
Highlights
Decoy receptor 3 (DcR3) has been shown to be a pleiotropic soluble factor to modulate cell functions via ‘decoy’ and ‘non-decoy’ actions [1]
The TL1A/death receptor 3 (DR3/TNFRSF25) axis is a novel immune pathway that participates in the pathogenesis of a variety of autoimmune rheumatic diseases [10], molecules involved in regulating TL1A/DR3 axis are regarded as promising therapeutic targets for various inflammatory and autoimmune diseases [12]
A greater number of missense DcR3 variants defective in secretion from cultured cells are identified by DNA sequencing. These observations suggest that these DcR3 variants may contribute to the pathogenesis of some inflammatory bowel disease (IBD) cases, and recombinant DcR3 may be able to attenuate alimentary tract inflammation in IBD patients. It is almost 19 years since the observation that DcR3 is overexpressed in various cancer cells and is able to neutralize Fas ligand (FasL)-mediated apoptosis [2]
Summary
DcR3 has been shown to be a pleiotropic soluble factor to modulate cell functions via ‘decoy’ and ‘non-decoy’ actions [1]. Inhibition of DcR3 expression may attenuate tumor growth, while enhancement of DcR3-mediated effector functions may become a promising approach to attenuate autoimmunity and promote tissue repairing. It has been demonstrated that human DcR3 is able to bind and neutralize the functions of mouse FasL, LIGHT, and TL1A [3].
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