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 LTR (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 LTR expression is prominent on epithelial cells but is absent in T and B lymphocytes. Signaling via LTR 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 LTR 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...
Among members of the tumor necrosis factor receptor (TNFR) superfamily, 4-1BB, CD27, and glucocorticoidinduced tumor necrosis factor receptor family-related gene (GITR) share a striking homology in the cytoplasmic domain. Here we report the identification of a new member, activation-inducible TNFR family member (AITR), which belongs to this subfamily, and its ligand. The receptor is expressed in lymph node and peripheral blood leukocytes, and its expression is up-regulated in human peripheral mononuclear cells mainly after stimulation with anti-CD3/CD28 monoclonal antibodies or phorbol 12-myristate 13-acetate/ionomycin. AITR associates with TRAF1 (TNF receptor-associated factor 1), TRAF2, and TRAF3, and induces nuclear factor (NF)-B activation via TRAF2. The ligand for AITR (AITRL) was found to be an undescribed member of the TNF family, which is expressed in endothelial cells. Thus, AITR and AITRL seem to be important for interactions between activated T lymphocytes and endothelial cells.
Key Words: atherosclerosis Ⅲ immunity Ⅲ tumor necrosis factor receptor superfamily 14 Ⅲ matrix metalloproteinases Ⅲ foam cells T umor necrosis factor (TNF)-␣ and CD40L play pivotal roles in the atherogenesis. TNF-␣ was found to be expressed in atherosclerotic plaques, 1,2 and TNF-␣ was also found to be colocalized with foam cells, smooth muscle cells (SMCs), 3,4 and mast cells. 5 CD40, a member of the TNF receptor superfamily (TNFRSF), is an integral membrane protein found on the surface of B lymphocytes, dendritic cells, hematopoietic progenitor cells, epithelial cells, and carcinomas. CD40 binds to a ligand (CD40L) which is a member of the TNF superfamily (TNFSF). 6 In atherosclerotic plaques, the expression of CD40L in T cells and the coexpression of CD40 and CD40L in vascular endothelial cells, SMCs, and macrophages were detected. 7 The interaction between CD40 and CD40L, similar to the interaction between TNF-␣ and its receptor, elicits diverse biological responses involved in atherosclerosis, such as the secretion of proinflammatory cytokines and matrix metalloproteinases (MMPs), and the expression of adhesion molecules and tissue factor. 8,9 These responses are known to make the plaque unstable. See page 1873Recently, the list of molecules belonging to TNFRSF has expanded significantly. TNFRSF14 (HVEM/HveA/ LIGHTR/TR2/ATAR) was initially identified as a cellular coreceptor for herpes simplex virus entry, hence, the name HVEM (herpes virus entry mediator, later named HveA [herpes virus entry protein A]). 10 TNFRSF14 has a wide tissue distribution and is prominently expressed by cells in lymphoid tissue, such as the spleen, and on peripheral blood leukocytes. TNFRSF14 mRNA was detected on resting and activated CD4ϩ and CD8ϩ T cells, on CD19ϩ B cells, and on monocytes. 14 We hypothesized that TNFRSF14, like the CD40/CD40L system, has a role in atherosclerosis. We analyzed the expression of TNFRSF14 in atherosclerotic plaques and the expression of proatherogenic cytokines and MMPs after stimulation of TNFRSF14 in THP-1 cells. Methods Histological AnalysisFor immunohistochemical analysis, carotid endarterectomy specimens were obtained from 13 patients, aged 63 to 81 years, who underwent the surgery at Samsung Seoul Hospital. The study was approved by an institutional review committee, and the subjects gave informed consent. Atherosclerotic plaque specimens were washed with saline and embedded in OCT (Miles Laboratories) to make frozen sections. Standard 5-m sections were stained by use of the LSAB kit (DAKO) according to the manual provided by the manufacturer. Double staining of CD68 and TNFRSF14 was performed by using an Animal Research Kit (DAKO) according to the manual provided by the manufacturer. Cell CultureHuman monocytic leukemia THP-1 cells 15 were obtained from the American Type Culture Collection. For the analysis of peripheral blood monocytes, whole blood was collected either in heparin Vacutainer or CTAD Diatubes (Becton Dickinson/Diagnostica Stago) containing dipyridamole and theophylline to pr...
Renal ischemia-reperfusion injury (IRI) after kidney transplantation is a major cause of delayed graft function. Even though IRI is recognized as a highly coordinated and specific process, the pathways and mechanisms through which the innate response is activated are poorly understood. In this study, we used a mouse model of acute kidney IRI to examine whether the interactions of costimulatory receptor CD137 and its ligand (CD137L) are involved in the early phase of acute kidney inflammation caused by IRI. We report here that the specific expressions of CD137 on natural killer cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the chemokine (C-X-C motif) receptor 2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. Our findings identify an innate pathogenic pathway for renal IRI involving the natural killer cell-TECneutrophil axis, whereby CD137-CD137L interactions provide the causal contribution of epithelial cell dysregulation to renal IRI. The CD137L reverse signaling pathway in epithelial cells therefore may represent a good target for blocking the initial stage of inflammatory diseases, including renal IRI.acute inflammation | costimulatory ligand
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