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...

Aims/hypothesis. Resistin is thought to be an important link between obesity and insulin resistance. It has been suggested that genetic polymorphism in the promoter of resistin gene is a determinant of resistin mRNA expression and possibly associated with obesity and insulin resistance. In this study, we investigated the association between the genotype of resistin promoter and its plasma concentrations. Methods. We examined g.-537A>C and g.-420C>G polymorphisms in the resistin promoter and measured plasma resistin concentrations in Korean subjects with or without Type 2 diabetes. We also did haplotypebased promoter activity assays and the gel electrophoretic mobility shift assay. Results. The −420G and the −537A alleles, which were in linkage disequilibrium, were associated with higher plasma resistin concentrations. Individuals with haplotype A-G (−537A and −420G) had significantly higher plasma resistin concentrations than the others. Haplotype A-G had modestly increased promoter activity compared to the other haplotypes. Electrophoretic mobility shift assay showed that the −420G allele is specific for binding of nuclear proteins from adipocytes and monocytes. However, none of the two polymorphisms were associated with Type 2 diabetes or obesity in our study subjects. Conclusions/interpretation. Polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans. [Diabetologia (2004) . Moreover, obese mice given an antiresistin antibody had increased insulin-stimulated glucose uptake, whereas the treatment of normal mice with recombinant resistin impaired insulin action [4]. Resistin therefore could link obesity with insulin resistance and diabetes in mouse models. However, subsequent studies in rodent models have produced disparate findings on the role of resistin in obesity and insulin resistance [5,6,7].In humans, the expression of resistin in adipocytes is much lower than that seen in rodents and does not differ between normal, insulin-resistant or Type 2 diabetic patients [8,9,10]. Little is known about the relationship between circulating resistin concentrations Resistin belongs to a novel family of cystein-rich C-terminal domain proteins called resistin-like molecules, which are identical to those found in inflammatory

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.

Resistin is an adipocyte-derived peptide that might play a role in obesity and insulin resistance. However, its role in humans is largely unclear. Although many studies have measured the expression of human resistin in tissues, the circulating concentrations of resistin and its relation to metabolic parameters in humans are unknown. We developed an ELISA for human resistin and measured plasma concentrations in aged individuals with or without type 2 diabetes mellitus. To validate the results of plasma resistin concentrations in our subjects, plasma adiponectin concentrations were also determined, which were higher in nondiabetic subjects than in type 2 diabetic patients and correlated with the homeostasis model assessment for insulin resistance (HOMA-IR). Log-transformed plasma resistin concentrations (log-resistin) were higher in diabetic patients compared with normal individuals (0.50 +/- 0.39 vs. 0.28 +/- 0.51 ng/ml; P < 0.001), and this difference was significant after controlling for gender and body mass index. Log-resistin did not show a significant correlation with HOMA-IR, waist circumference, body mass index, blood pressure, or total cholesterol. The plasma glucose concentration was an independent factor associated with log-resistin. In conclusion, plasma resistin concentrations are elevated in patients with type 2 diabetes, but are not associated with insulin resistance or obesity.