Induction of Apoptosis by Apo-2 Ligand, a New Member of the Tumor Necrosis Factor Cytokine Family

Abstract

Cytokines in the tumor necrosis factor (TNF) family regulate development and function of the immune system. We have isolated a new member of this family, designated Apo-2 ligand (Apo-2L), via an expressed sequence tag. Apo-2L is a 281-amino acid protein, related most closely to Fas/Apo-1 ligand. Transfected Apo-2L is expressed at the cell surface with its C terminus exposed, indicating a type II transmembrane protein topology. Like Fas/Apo-1 ligand and TNF, the C-terminal extracellular region of Apo-2L (amino acids 114 -281) exhibits a homotrimeric subunit structure. Soluble Apo-2L induces extensive apoptosis in lymphoid as well as non-lymphoid tumor cell lines. The effect of Apo-2L is not inhibited by soluble Fas/Apo-1 and TNF receptors; moreover, expression of human Fas/Apo-1 in mouse fibroblasts, which confers sensitivity to induction of apoptosis by agonistic anti-Fas/Apo-1 antibody, does not confer sensitivity to Apo-2L. Hence, Apo-2L acts via a receptor which is distinct from Fas/Apo-1 and TNF receptors. These results suggest that, along with other family members such as Fas/Apo-1 ligand and TNF, Apo-2L may serve as an extracellular signal that triggers programmed cell death. TNF1 family cytokines modulate host defense mechanisms via a corresponding family of receptors (1-3). Most TNF family cytokines are expressed as type II transmembrane proteins, whose C-terminal extracellular domain is processed proteolytically to form a soluble homotrimeric molecule. In contrast, the members of the TNF receptor (TNFR) family are type I transmembrane proteins. In both families, sequence homology is found mainly in the extracellular regions, which mediate ligand-receptor binding.Members of the TNF family have diverse biological actions, including T cell co-stimulation, induction of B cell proliferation and differentiation, and macrophage activation (1-3). In addition, certain TNF family members regulate the elimination of unwanted immune cells by inducing programmed cell death (apoptosis). For example, Fas/Apo-1 ligand (Fas/Apo-1L) plays a key role in peripheral deletion of self-reactive lymphocytes, as suggested by the autoimmune phenotype of the mouse mutations lpr and gld, which occur, respectively, in the Fas/Apo-1 receptor or ligand genes (4, 5). In addition, Fas/Apo-1L is involved in apoptosis of B cells and CD4 ϩ T cells subsequent to stimulation by antigen, while TNF mediates a similar function in CD8ϩ T cells (4 -7). In this article, we describe a new member of the TNF cytokine family. We have designated this protein Apo-2L, because it resembles the Fas/Apo-1L in its amino acid sequence, as well as in its ability to induce apoptosis. Apo-2L appears to act via a receptor which is distinct from Fas/Apo-1 and TNF receptors, suggesting that its biological role is unique. EXPERIMENTAL PROCEDURESCloning of Apo-2L cDNA-To isolate a full-length cDNA that contains the sequence of expressed sequenced tag (EST) HHEA47M, a gt11 bacteriophage library of human placental cDNA (ϳ1 ϫ 10 6 clones) (HL1075b, Clontech) was screene...

TRAIL in the mandarin fish Siniperca chuatsi: Gene and its apoptotic effect in HeLa cells

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Effect of bevacizumab plus XELOX (CapeOX) chemotherapy on liver natural killer cell activity in colorectal cancer with resectable liver metastasis

“…Furthermore, the proportion of TRAIL‐positive NK cells in LMNC significantly increased in the neoadjuvant chemotherapy group. Studies have shown TRAIL to be critical among tumor necrosis factor (TNF) family members in the NK cell‐mediated antitumor function 20, 43. Moreover, CRC cells are susceptible to TRAIL‐induced apoptosis, both as a single agent of recombinant TRAIL and combined with chemotherapy and targeted therapies 44.…”

Intra-articular adenoviral-mediated gene transfer of trail induces apoptosis of arthritic rabbit synovium

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“…TRAIL is a type II transmembrane protein of the TNF-a superfamily that was initially discovered due to its sequence homology with TNF-a and FasL. 13,14 Similar to FasL and TNF-a, TRAIL has demonstrated the ability to induce a potent apoptotic response in susceptible cells. 16 TRAIL induces apoptosis by binding to and cross-linking death-domain containing receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5).…”