title: Characterization of the in vivo function of TNF-alpha-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 differentiation of 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.
authors.affiliation: Department of Molecular Immunology, Immunex Corporation, Seattle, USA. Lisa_Sedger@wmmi.usyd.edu.au
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sedger
authors.forename: Moira B
authors.initials: MB
authors.lastname: Glaccum
authors.forename: JoAnn C L
authors.initials: JC
authors.lastname: Schuh
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Kanaly
authors.forename: Eilidh
authors.initials: E
authors.lastname: Williamson
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.forename: Theordore
authors.initials: T
authors.lastname: Yun
authors.forename: Pam
authors.initials: P
authors.lastname: Smolak
authors.forename: Tiep
authors.initials: T
authors.lastname: Le
authors.forename: Ray
authors.initials: R
authors.lastname: Goodwin
authors.forename: Brian
authors.initials: B
authors.lastname: Gliniak
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015519:Bone Density; D005260:Female; D006023:Glycoproteins / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology; D010010:Osteoclasts / Q000502:physiology; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C506031:Tnfrsf11b protein, mouse; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha