A Newly Identified Member of Tumor Necrosis Factor Receptor Superfamily (TR6) Suppresses LIGHT-mediated Apoptosis

Abstract

TR6 (decoy receptor3The members of the tumor necrosis factor (TNF) 1 family are involved in regulating diverse biological activities such as regulation of cell proliferation, differentiation, cell survival, cell death, cytokine production, lymphocyte co-stimulation, and isotype switching (1, 2). Receptors in this family share a common structural motif in their extracellular domains consisting of multiple cysteine-rich repeats of approximately 30 -40 amino acids (3). While TNFR1, CD95/Fas/APO-1, DR3/TRAMP/ APO-3, DR4/TRAIL-R1/APO-2, DR5/TRAIL-R2, and DR6 receptors contain a conserved intracellular motif of ϳ80 amino acids called death domain, associated with the activation of apoptotic signaling pathways, other members, which contain a low sequence identity in the cytoplasmic domains, stimulate the transcription factors NF-B and AP-1 (1-3).Most TNF receptors contain a functional cytoplasmic domain. However, some members of the TNFR superfamily do not have cytoplasmic domains and are secreted, such as osteoprotegerin (OPG) (4), or linked to the membrane through a glycophospholipid tail, such as TRID/DcR1/TRAIL-R3 (5, 6). Viral open reading frames encoding soluble TNFRs have also been identified, such as SFV-T2 (7), Va53 (8), G4RG (9), and crmB (3).By searching an expressed sequence tag (EST) data base, a new member of the TNFR superfamily was identified, named TR6, and was characterized as a soluble cognate receptor for LIGHT and FasL/CD95L. LIGHT and FasL mediate the apoptosis, which is the most common physiological form of cell death and occurs during embryonic development, tissue remodeling, immune regulation, and tumor regression.LIGHT is highly induced in activated T lymphocytes and macrophages. LIGHT was characterized as a cellular ligand for HVEM/TR2 and LT␤R (10). HVEM/TR2 is a receptor for herpes simplex virus type 1 (HSV-1) entry into human T lymphoblasts. The soluble form of HVEM/TR2-Fc and antibodies to HVEM/ TR2 were shown to inhibit a mixed lymphocyte reaction, suggesting a role for this receptor or its ligand in T lymphocyte proliferation (10 -12). The level of LT␤R expression is prominent on epithelial cells but is absent in T and B lymphocytes. Signaling via LT␤R triggers cell death in some adenocarcinomas (13). LIGHT produced by activated lymphocytes could evoke immune modulation from hematopoietic cells expressing only HVEM/TR2 and induce apoptosis of tumor cells, which express both LT␤R and HVEM/TR2 receptors (14,15).FasL is one of the major effectors of cytotoxic T lymphocytes and natural killer cells. It is also involved in the establishment of peripheral tolerance in the activation-induced cell death of lymphocytes. Moreover, expression of FasL in nonlymphoid and tumor cells contributes to the maintenance of immune privilege of tissues by preventing the infiltration of Fas-sensitive lymphocytes (16). FasL is also processed and shed from the surface of human cells (17).Here we demonstrate that TR6 (DcR3), a new member of the TNFR superfamily, binds LIGHT and FasL. Therefore TR6 may act as a...

Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

“…from five independent experiments. * Po0.05 as compared with control without DcR3 and cytokine treatment mediator (HVEM), 21,44 is released from activated macrophages. Since macrophages bear both LTbR and HVEM, which mediate the NF-kB signaling pathway, the possibility for DcR3-mediated osteoclastogenesis resulting from the neutralization of LIGHT was considered.…”

“…12,[15][16][17] The pleiotropic cytokine TNF-a has been implicated in the pathogenesis of osteoclastogenesis via the activation of TNF receptor 1 (TNFR1). 15,18,19 Decoy receptor 3 (DcR3) is a member of the TNF receptor superfamily and has been shown to be the decoy receptor for Fas ligand (FasL), 20 LIGHT, 21 and TL1A. 22 DcR3 lacks a transmembrane domain and is regarded as a secreted molecule.…”

LIGHT, a new TNF superfamily member, is essential for memory T helper cell‐mediated activation of dendritic cells

“…Functionally, LIGHT can induce apoptosis of some tumor cells in vitro [13], via lymphotoxin g receptor triggering [14], and in vivo [11]. Decoy receptor 3 (DcR3, TR6), a soluble receptor for LIGHT, inhibits LIGHT-mediated apoptosis [15] and can presumably modulate other LIGHT functions. Through its interaction with Herpes virus entry mediator (HVEM), LIGHT can costimulate T cell activation [12,13].…”

Expression of TNFRSF6B in kidneys is a novel predictor for progression of chronic kidney disease

“…8 TNFRSF6B could act as decoy receptor to neutralize the proapoptotic effects of Fas ligand, LIGHT, and tumor necrosis factorlike molecule 1A by blocking the interaction with their respective receptors and evading immune surveillance. [8][9][10] Overexpression of TNFRSF6B, originally found in lung and colon cancers and virus-associated lymphoma, is capable of protecting cancer cells against apoptosis. 11 Mounting evidences have shown that TNFRSF6B overexpression is a novel tissue biomarker for predicting tumor invasion and worsening of various chronic inflammatory diseases.…”