Alternative titles; symbols
HGNC Approved Gene Symbol: TNFSF10
Cytogenetic location: 3q26.31 Genomic coordinates (GRCh38): 3:172,505,508-172,523,430 (from NCBI)
Tumor necrosis factor (TNF) family cytokines function as prominent mediators of immune regulation and the inflammatory response. Most TNF family cytokines are expressed as type II transmembrane proteins, with homology confined to approximately 150 C-terminal residues. The TNF ligands interact with a parallel family of receptors.
By searching an EST database with a sequence from a conserved region of TNF family members, Wiley et al. (1995) identified a cDNA encoding 'TNF-related apoptosis-inducing ligand' (TRAIL), a novel TNF family protein. The predicted 281-amino acid TRAIL protein has the characteristic structure of a type II membrane protein, with a single internal hydrophobic domain and no signal sequence. The extracellular C-terminal domain of TRAIL shares 22 to 28% identity with the C-terminal domains of the TNF family members FAS ligand (FASL; 134638), TNF-alpha (191160), LT-alpha (153440), and LT-beta (600978). Northern blot analysis revealed that the predominant 1.8- to 2.0-kb TRAIL mRNA is expressed in many human tissues. Independently, Pitti et al. (1996) isolated cDNAs encoding TRAIL, which they called APO2L for APO2 ligand.
Wiley et al. (1995) cloned mouse Trail cDNAs. The deduced mouse and human TRAIL proteins are 65% identical.
By microarray analysis, Jun et al. (2001) demonstrated expression of the TNFSF10 gene in human donor corneas.
By genomic sequence analysis, Gong and Almasan (2000) showed that, in contrast to other TNF family members, the TRAIL gene promoter lacks TATA and CAAT boxes but does become active in response to IFNA and IFNB but not IFNG. TRAIL spans approximately 20 kb and contains 5 exons.
By fluorescence in situ hybridization, Wiley et al. (1995) mapped the TNFSF10 gene to chromosome 3q26.
Wiley et al. (1995) showed that both cell-bound TRAIL and an engineered soluble form rapidly induced apoptosis in a wide variety of transformed cell lines of diverse origin.
Degli-Esposti et al. (1997) noted that TRAIL can induce apoptosis in a wide variety of transformed cell lines of diverse lineage, but does not appear to kill normal cells even though TRAIL mRNA is expressed at significant levels in most normal tissues. They suggested that the regulation of TRAIL function takes place at the level of receptor expression. The TRAIL receptors TRAILR1, also called DR4 (603611), and TRAILR2, also called DR5 (603612), are capable of mediating apoptosis. Two other receptors, TRAILR3 (603613) and TRAILR4 (TNFRSF10D; 603614), do not signal apoptosis and are potential decoy receptors for TRAIL.
Cell death induced by TRAIL had been believed to occur exclusively in tumor cells, suggesting that this drug was safe to use as an antitumor therapy. Nitsch et al. (2000) reported that TRAIL induced apoptosis in the human brain, which argues against the use of TRAIL for therapy of human brain tumors. However, neuroinflammatory T cells that express TRAIL might induce apoptosis of brain tissue, indicating a potential target for treatment of multiple sclerosis.
Gong and Almasan (2000) reported that TRAIL mRNA is upregulated in response to IFNA (147660) and IFNB (147640), but not IFNG (147570), in Jurkat and multiple myeloma cells.
Cytomegalovirus (CMV) is a persistent viral pathogen that resides in monocyte/macrophages and dendritic cells (DCs), critical antigen-presenting cells in the immune system. In fetal and compromised immune systems, CMV can be fatal. Raftery et al. (2001) found that recent CMV isolates, but not fibroblast-adapted CMV strains, could infect mature DCs with no change in some cell surface markers. On the other hand, flow cytometric analysis indicated a slight upregulation of the costimulatory molecules CD40 (109535), CD80 (112203), and CD86 (601020), as well as a downregulation of MHC class I and class II molecules. Functional analysis showed that CMV-infected mature DCs suppress T-cell proliferation. Further FACS analysis demonstrated an upregulation of TRAIL and FASL, molecules that induce T-cell apoptosis through caspase (see CASP8; 601763)-dependent mechanisms, on DCs. Raftery et al. (2001) concluded that CMV evades the immune response by first downregulating MHC antigens, thereby diminishing T-cell responses, followed by an upregulation of apoptosis-inducing ligands that delete activated T cells. They also proposed that nondeletional, possibly cytokine-mediated mechanisms are involved in T-cell suppression.
By flow cytometric, immunocytochemical, and immunohistochemical analyses, Robertson et al. (2002) found that TRAIL expression and eosinophil numbers were significantly increased in bronchoalveolar lavage fluid, in epithelial, airway smooth muscle, and vascular smooth muscle cells, and throughout the interstitial tissue of asthmatic patients compared with nonasthmatic subjects after segmental antigen challenge (SAC). Increased expression of the TRAIL decoy receptor DCR2 (TNFRSF10D) and decreased expression of the TRAIL receptors DR4 and DR5 was observed after SAC in asthma patients compared with controls. Robertson et al. (2002) proposed that modulation of TRAIL and TRAILR interactions after antigen provocation may be crucial in promoting eosinophil survival in asthma.
By targeted deletion, Cummins et al. (2004) disrupted the XIAP gene (300079) in human colon cancer cells. Deletion of the XIAP gene did not interfere with basal proliferation, but enhanced sensitivity to exogenously added TRAIL. TRAIL increased apoptosis in both XIAP knockout cells and wildtype cells, but the increase was markedly greater in knockout cells. The increased apoptosis in knockout cells correlated with higher levels of cleaved caspase-3 (CASP3; 600636), but not of CASP7 (601761) or CASP9 (602234), compared with wildtype cells. Over a broad range of TRAIL doses, XIAP knockout cells exhibited reduced clonogenic survival and proliferation. Cummins et al. (2004) concluded that XIAP is a nonredundant modulator of TRAIL-mediated apoptosis.
Janssen et al. (2005) explored the instructional program that governs the secondary response of CD8+ (see 186910) T cells and found that 'helpless' cells (which, when primed in the absence of CD4+ T cells, can mediate effector functions such as cytotoxicity and cytokine secretion upon restimulation but do not undergo a second round of clonal expansion) undergo death by activation-induced cell death upon secondary stimulation. This death is mediated by TRAIL. Regulation of TRAIL expression can therefore account for the role of CD4+ (186940) T cells in the generation of CD8+ T cell memory and represents a novel mechanism for controlling adaptive immune responses.
Herbeuval et al. (2005) noted that TRAIL induces apoptosis in primary CD4-positive T cells exposed to human immunodeficiency virus (HIV)-1 in vitro in an IFNA/IFNB-dependent manner, and that HIV-1-infected patients have elevated plasma TRAIL levels. Using flow cytometry, Herbeuval et al. (2005) found that IFNA/IFNB or HIV-1 induced expression of TRAIL on CD4-positive T-cell membranes. TRAIL expression was accompanied by increased STAT2 (600556) levels and expression of phosphorylated STAT1 (600555), and Herbeuval et al. (2005) identified plasmacytoid DCs as the IFN source. Production of IFNA by plasmacytoid DCs could be blocked by inhibiting binding of the HIV-1 gp120 protein to CD4, but not by inhibiting binding of gp120 to viral coreceptors (i.e., CCR5; 601373). Culturing CD4-positive T cells from HIV-1-infected patients in the presence of anti-IFNA/IFNB resulted in reduced TRAIL expression, irrespective of type of antiretroviral therapy.
Using flow cytometric analysis, Herbeuval et al. (2006) found that HIV-positive patients had reduced circulating CD123 (308385)-positive plasmacytoid DCs in blood compared with HIV-negative controls. However, HIV-positive patients had higher secretion of IFNA, higher cytoplasmic expression of MYD88 (602170) and IRF7 (605047), and higher surface expression of CCR7 (600242), suggesting migration of plasmacytoid DCs to lymph nodes. Immunohistochemical analysis showed high IFNA expression in T cell-rich areas of lymphoid tonsillar tissue of HIV-positive patients. RT-PCR analysis showed that expression of TRAIL and FASL, as well as that of their receptors, was significantly higher in lymphoid tonsillar tissue of patients with progressive HIV disease compared with patients with nonprogressive disease and HIV-negative controls, and TRAIL expression correlated with plasma viral load. Herbeuval et al. (2006) concluded that the TRAIL and FASL apoptotic pathways are activated in more advanced HIV disease.
Weckmann et al. (2007) found that allergen-sensitized and -challenged mice lacking Trail or treated with small interfering RNA targeting Trail did not develop airway hyperreactivity (AHR). These mice showed impaired production of Ccl20 (601960), resulting in reduced inflammation and less homing of myeloid DCs and T cells expressing Ccr6 (601835) and Cd4 to airways. Delivery of recombinant Trail to naive wildtype mice caused development of AHR accompanied by mucus hypersecretion and eosinophil and mast cell influx within 24 hours. Isolated peribronchial lymph node cells from Trail-treated mice released increased Il13 (147683) and Il5 (147850) compared with controls. Il13 -/- mice treated with Trail did not develop AHR. Levels of TRAIL were increased in sputum from asthmatic patients compared with controls, and adult asthmatics had higher levels of TRAIL than asthmatic children. Bronchial epithelial cells from asthmatic patients released more CCL20 in a TRAIL dose-dependent manner compared with controls. Weckmann et al. (2007) proposed that TRAIL promotes homing of DCs and T helper-2 (Th2) cells to airways of asthmatic individuals.
Spencer et al. (2009) imaged sister cells expressing reporters of caspase activation and mitochondrial outer membrane permeabilization after exposure to TRAIL. They showed that naturally occurring differences in the levels or states of proteins regulating receptor-mediated apoptosis are the primary causes of cell-to-cell variability in the timing and probability of death in human cell lines. Protein state is transmitted from mother to daughter, giving rise to transient heritability in fate, but protein synthesis promotes rapid divergence so that sister cells soon become no more similar to each other than pairs of cells chosen at random. Spencer et al. (2009) concluded that their results have implications for understanding 'fractional killing' of tumor cells after exposure to chemotherapy, and for variability in mammalian signal transduction in general.
Zhang et al. (2010) showed that deficiency in the APC gene (611731) and subsequent activation of beta-catenin (116806) lead to the repression of cellular caspase-8 inhibitor c-FLIP (603599) expression through activation of c-Myc (190080), and that all trans-retinyl acetate (RAc) independently upregulates TRAIL death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, Zhang et al. (2010) showed that short-term and noncontinuous TRAIL and RAc treatment induced apoptosis specifically in intestinal polyps, strongly inhibited tumor growth, and prolonged survival in 'multiple intestinal neoplasms' (Min) mice. With their approach, Zhang et al. (2010) further demonstrated that TRAIL and RAc induced significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.
Crystal Structure
Formation of a complex between APO2L and its signaling receptors, DR4 and DR5, triggers apoptosis by inducing the oligomerization of intracellular death domains. Hymowitz et al. (1999) reported the crystal structure of the complex between APO2L and the ectodomain of DR5. The structure shows 3 elongated receptors snuggled into long crevices between pairs of monomers of the homotrimeric ligand. The interface is divided into 2 distinct patches, one near the bottom of the complex close to the receptor cell surface and the other near the top. Both patches contain residues that are critical for high-affinity binding. A comparison to the structure of the lymphotoxin receptor complex (see 600979) suggested general principles of binding and specificity for ligand recognition in the TNF receptor superfamily.
Yan et al. (2009) reported that soluble TRAIL (sTRAIL) concentrations in 84 Chinese patients with nonalcoholic fatty liver disease (NAFLD; see 613282) were significantly higher than in controls. Furthermore, sTRAIL levels were positively correlated with triglyceride concentrations in NAFLD patients. Risk of fatty liver disease attack was lower in patients who were homozygous for 1525G-A and 1595C-T SNPs in the 3-prime UTR of the TRAIL gene. These SNPs were in complete linkage disequilibrium in the Chinese population.
Cretney et al. (2002) generated healthy, fertile Trail-deficient mice by homologous recombination. Functional analysis confirmed the importance of Trail in mediating natural killer (NK) cytotoxicity to some tumor target cells. The authors found that Trail contributes to natural killer (NK) cell suppression of metastases to liver by a renal adenocarcinoma and to multiple tissues by breast carcinoma cells. Trail -/- mice were also more susceptible than wildtype mice to early onset of fibrosarcomas from lower doses of methylcholanthrene.
Schmaltz et al. (2002) studied the potential role of TRAIL in donor T cell-mediated graft-versus-tumor activity by comparing donor T cells from Trail-deficient and wildtype mice in clinically relevant mouse bone marrow transplantation models. Schmaltz et al. (2002) found that alloreactive T cells could express Trail, but the absence of Trail had no effect on their proliferative and cytokine response to alloantigens. Trail-deficient T cells showed significantly lower graft-versus-tumor activity than did Trail-expressing T cells, but no important differences in graft-versus-host disease (GVHD; see 614395) were observed.
Lamhamedi-Cherradi et al. (2003) found that thymocyte deletion was severely impaired following T-cell receptor ligation in mice deficient in Trail. In addition, Trail -/- mice were hypersensitive to collagen-induced arthritis and streptozotocin-induced diabetes. Lamhamedi-Cherradi et al. (2003) concluded that a link between defective thymic negative selection and enhanced susceptibility to autoimmune disease remained to be established.
Using 2 experimental models of hepatitis, Zheng et al. (2004) found that hepatic cell death in vivo was dramatically reduced in Trail-deficient mice and mice treated with a blocking Trail receptor. Although both Trail and its death receptor-5 were constitutively expressed in the liver, Trail expression by immune cells alone was sufficient to restore the sensitivity of Trail-deficient mice to hepatitis. The authors concluded that TRAIL plays a crucial role in hepatic cell death and hepatic inflammation.
Zerafa et al. (2005) found that a third of Trail -/- mice developed spontaneous malignancies, mostly lymphomas, over an 850-day period. More than 75% of Trail -/- mice heterozygous for p53 (TP53; 191170) developed tumors. No critical role for Trail in Her2 (ERBB2; 164870) oncogene-driven mammary cell carcinoma could be discerned. Zerafa et al. (2005) concluded that TRAIL has a significant role in controlling carcinogenesis, but its role in epithelial malignancies is not clear.
Hoffmann et al. (2007) detected elevated levels of soluble TRAIL in the cerebrospinal fluid (CSF) of patients with bacterial meningitis. Trail -/- mice showed delayed leukocyte influx into the CSF and prolonged inflammation in response to pneumococcal cell wall, a model of experimental meningitis, compared with wildtype mice. Trail -/- mice also exhibited higher levels of both pro- and antiinflammatory cytokines, greater numbers of apoptotic cells in the dentate gyrus, and clinically observable functional deficits during meningitis. Administration of recombinant Trail resulted in markedly decreased CSF leukocyte counts and reduced apoptosis in hippocampus after induction of meningitis in both wildtype and Trail -/- mice. Hoffmann et al. (2007) concluded that TRAIL is a modulator of granulocyte-driven inflammation that limits the life span of activated leukocytes through its proapoptotic activities. TRAIL also enhances granulocyte recruitment and may have potential for terminating an acute inflammatory response during invasive infections.
Brincks et al. (2011) found that influenza A virus (IAV)-infected Trail -/- mice exhibited increased morbidity and mortality compared with wildtype mice, despite similar rates of viral clearance. Trail -/- mice also showed increased pulmonary pathology and inflammatory chemokine production. Increased numbers of IAV-specific CD8 T cells, high cytotoxic activity, and decreased apoptosis were observed in lungs of infected Trail -/- mice. Brincks et al. (2011) concluded that TRAIL regulates the magnitude of the IAV-specific CD8 T-cell response during a clinically significant IAV infection to decrease the chance for infection-induced immunopathology.
Schuster et al. (2014) found that a population of NK cells expressing Trail accumulated specifically in mouse salivary gland during chronic infection with murine CMV (MCMV) and delayed clearance of the virus. Immunohistochemical analysis demonstrated that salivary gland NK cells were in close proximity and interacted with Cd4-positive T cells after MCMV infection. Mice lacking Trail had much higher numbers of Cd4-positive T cells, but not Cd8-positive T cells. Trail-positive NK cells also expressed increased Nkg2d (KLRK1; 611817), and Cd4-positive cells expressed Nkg2d ligands (e.g., MICA; 600169). Trail -/- mice depleted of Cd4-positive cells, but not Cd8-positive cells, had increased viral load in salivary gland. Depletion of NK cells resulted in lower viral burden but increased Sjogren syndrome (270150)-like autoimmunity characterized by focal lymphocytic infiltration into salivary gland. Schuster et al. (2014) concluded that Trail-positive NK cells constrain the elimination of MCMV and the development of MCMV-induced autoimmunity and are an important homeostatic control in response to viral infection.
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