Selective Induction of Tumor Necrosis Receptor Factor 6/Decoy Receptor 3 Release by Bacterial Antigens in Human Monocytes and Myeloid Dendritic Cells

Abstract

Tumor necrosis factor (TNF) receptor 6 (TR6), also called decoy receptor 3 (DcR3) or M68, is a member of the TNF receptor family that is produced as a secreted protein (3,25,35). Similar to other members of the family, TR6 binds with high affinity to multiple ligands, including Fas ligand (FasL), LIGHT, and TL1A (18,25,35). Since TR6 lacks a transmembrane domain, it can function as an inhibitor by competing with the signal-transducing receptor for the ligand. The recombinant protein was indeed able to inhibit in vitro and in vivo FasL-induced apoptosis (5, 25). Because of TR6 overexpression in a substantial number of tumors (23, 28), it has been postulated that the decoy receptor promotes the survival of tumor cells by helping them to escape FasL-dependent cell death (3, 25). In addition, several studies have suggested a role for TR6 in immunity, through the modulation of T-cell responses. TR6 was found to inhibit the interaction of TL1A, a T-cell costimulatory cytokine, with its receptor DR3 (18). Soluble protein was also shown to downmodulate the cytotoxic activity of T lymphocytes and ameliorate heart allograft rejection in mice, possibly by interfering with LIGHT/TR2 binding (36). In another study, solid-phase TR6 was reported to stimulate proliferation and cytokine production in T lymphocytes by reverse signaling through LIGHT (32). Lastly, TR6 was reported to modulate dendritic cell maturation (10).Little is known about the regulation of TR6 expression in nonmalignant cells. TR6 mRNA is expressed in endothelial cells and keratinocytes (16,35), and the protein was detected in epithelial cells of the colon (3). The mRNA was also detected at low levels in other healthy human tissues, such as stomach, lymph node, lung, and spleen tissues (3). The involvement of TR6 in immune responses raised the possibility that the expression of the protein may be regulated in cells of the immune system. Therefore, the aim of our study was to investigate the expression and release of TR6 by immune cells. MATERIALS AND METHODSReagents. Cytokines were purchased from PeproTech (Rocky Hill, N.J.); Staphylococcus aureus Cowan I, PD98059, SB203580, herbimycin A, and wortmannin were purchased from Calbiochem (San Diego, Calif.); phytohemagglutinin (PHA), lipopolysaccharide (LPS), and lipoteichoic acids (LTA) were purchased from Sigma-Aldrich (St. Louis, Mo.); and CD40 ligand (CD40L) and a TNF-␣ enzyme-linked immunosorbent assay (ELISA) kit were purchased from R&D Systems (Minneapolis, Minn.).Cell cultures. Monocytes were obtained from human peripheral blood mononuclear cells (PBMC) by centrifugation of leukopheresis preparations (BRT Inc., Baltimore, Md.) through Histopaque gradients (Sigma-Aldrich) followed by counterflow centrifugal elutriation. Cell purity was greater than 92%. Cells were cultured in complete medium consisting of RPMI 1640 medium (GIBCO BRL, Rockville, Md.) supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, and 50 g of gentamicin (Biofluids Inc., Rockville, Md.)/ml. Myeloid dendritic cel...

Decoy Receptor 3, a Novel Inflammatory Marker, and Mortality in Hemodialysis Patients

“…The origin of DcR3 in CKD patients is unknown, although studies have suggested that endothelium and bacterial antigen-stimulated immune cells can secrete DcR3 protein (23). In accordance with previous reports, our study confirms that serum concentrations of DcR3 are elevated in patients with CKD compared with those in healthy individuals (12).…”

Attenuation of Th1 Response in Decoy Receptor 3 Transgenic Mice

“…Wu et al (8) reported that 56% of tumor patients are serum DcR3 positive, and Ͼ70% of patients with gastric, liver, and gallbladder carcinomas have elevated serum DcR3 levels (Ͼ20 pg/ml). In addition, overexpression of DcR3 has been reported in cases of silicosis or systemic lupus erythematosus (9) as well as in bacterial Ag-stimulated monocytes and myeloid DCs (10). DcR3 can block the effects of its known ligands (FasL, LIGHT, and TL1A) and contributes to tumor growth by impeding the immune response as well as inducing angiogenesis (11).…”

Inhibition of Lymphotoxin-β Receptor–Mediated Cell Death by Survivin-ΔEx3

“…LIGHT is able to interact with lymphotoxin-h receptor (LThR) to induce cell death (2)(3)(4) or with HVEM to modulate immune cell functions (5-7). Moreover, LIGHT interacts with decoy receptor 3 (8), a soluble receptor overexpressed by tumor cells (9) and activated dendritic cells (10). LIGHT enhances IFN-g secretion by activated T cells (11), and IFN-g potentiates LIGHT-mediated cell death in MDA-MB-231 human breast cancer cells (7,12) as well as in p53-deficient HT-29 human adenocarcinoma cells (13)(14)(15) and Hep3BT2 human hepatoma cells (16,17).…”