Characterization of the in vivo function of TNF-α-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice

Abstract

To define the normal physiological role for the TRAIL/Apo2L in vivo, we generated TRAIL/Apo2L gene‐targeted mice. These mice develop normally and show no defects in lymphoid or myeloid cell homeostasis or function. Although TRAIL/Apo2L kills transformed cells in vitro, TRAIL/Apo2L–/– mice do not spontaneously develop overt tumors at an early age. However, in the A20 B cell lymphoma‐transferred tumor model, TRAIL/Apo2L–/– mice are clearly more susceptible to death from overwhelming tumor burden, due to increased lymphoma load in the liver. A20 tumors are susceptible to TRAIL/Apo2L killing in vitro, indicating that TRAIL/Apo2L may act directly to control A20 cells in vivo. Despite the fact that TRAIL binds osteoprotegerin and osteoprotegerin‐transgenic mice are osteopetrotic, TRAIL/Apo2L–/– mice show no evidence of altered gross bone density, and no alterations in frequency or in vitro differentiationof bone marrow precursor osteoclasts. Moreover, leucine zipper TRAIL has no toxicity when repeatedly administered to osteoprotegerin–/– mice. Thus, TRAIL/Apo2L is important in controlling tumors in vivo, but is not an essential regulator of osteoprotegerin‐mediated biology, under normal physiological conditions.

BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

“…First, TRAIL knockout mice are more susceptible to tumorigenesis induced by chemical carcinogens and metastasis Sedger et al, 2002). Second, experiments that used neutralizing antibodies against TRAIL demonstrated that it could significantly increase liver metastases in mice Clarke et al, 2004).…”

“…TRAIL is critically involved in anti-cancer surveillance by immune cells (Takeda et al, 2001(Takeda et al, , 2004Schmaltz et al, 2002) and also has the ability to trigger apoptosis in a cell autonomous way, in a variety of tumor cell lines, but not in most normal cells (Walczak et al, 1999;Wang and El-Deiry, 2003). Importantly, TRAIL À/À mice display an increased susceptibility to tumor initiation and metastasis Sedger et al, 2002), highlighting the importance of TRAIL in the defense against tumors. Therefore, it is not surprising that one of the key mechanisms of tumor escape is a general downregulation of TRAIL.…”

Rheumatoid arthritis synovial fluid macrophages express decreased tumor necrosis factor–related apoptosis‐inducing ligand R2 and increased decoy receptor tumor necrosis factor–related apoptosis‐inducing ligand R3

“…Additionally, macrophages (22) were deleted by autologous CD4ϩ T cells in part through a TRAIL-mediated pathway. However, TRAIL-deficient mice displayed no abnormalities in immune function or development (27). Thus, the role of TRAIL in regulating hematopoietic cell homeostasis remains unclear.…”

TRAIL and immunity: more than a license to kill tumor cells

“…26 Interestingly, however, while Fas (lpr) and FasL (gld) mutant mice show clear symptoms of uncontrolled immune cell activation, defects in cellular homeostasis, reduced apoptosis and development of autoimmune disease, 27 none of these signs is obvious in the TRAIL-deficient mouse, at least not at the first glance. 28,29 Yet, a more detailed analysis revealed that lack of TRAIL predisposes to increased susceptibility to the development of autoimmune diseases. For example, C57BL/6 mice are usually resistant to collagen-induced arthritis but develop severe disease in the absence of TRAIL expression.…”