title: Multiple members of the TNF superfamily contribute to IFN-gamma-mediated inhibition of erythropoiesis.
abstract: IFN-gamma inhibits the growth and differentiation of erythroid precursor cells and mediates hemopoietic suppression through mechanisms that are not completely understood. We found that treatment of human erythroid precursor cells with IFN-gamma up-regulates the expression of multiple members of the TNF family, including TRAIL and the recently characterized protein TWEAK. TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) were expressed by purified erythroblasts at all the stages of maturation. Exposure to recombinant TWEAK or agonist anti-Fn14 Abs was able to inhibit erythroid cell growth and differentiation through caspase activation. Because other members of the TNF family such as TRAIL and CD95 ligand (CD95L) are known to interfere with erythroblast growth and differentiation, we investigated the role of different TNF/TNFR family proteins as potential effectors of IFN-gamma in the immature hemopoietic compartment. Treatment of erythroid precursor cells with agents that blocked either TRAIL, CD95L, or TWEAK activity was partially able to revert the effect of IFN-gamma on erythroid proliferation and differentiation. However, the simultaneous inhibition of TRAIL, TWEAK, and CD95L resulted in a complete abrogation of IFN-gamma inhibitory effects, indicating the requirement of different receptor-mediated signals in IFN-gamma-mediated hemopoietic suppression. These results establish a new role for TWEAK and its receptor in normal and IFN-gamma-mediated regulation of hematopoiesis and show that the effects of IFN-gamma on immature erythroid cells depend on multiple interactions between TNF family members and their receptors.
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Nadia
authors: N
authors: Felli
authors: Francesca
authors: F
authors: Pedini
authors: Ann
authors: A
authors: Zeuner
authors: Eleonora
authors: E
authors: Petrucci
authors: Ugo
authors: U
authors: Testa
authors: Concetta
authors: C
authors: Conticello
authors: Mauro
authors: M
authors: Biffoni
authors: Andrea
authors: A
authors: Di Cataldo
authors: Jeffrey A
authors: JA
authors: Winkles
authors: Cesare
authors: C
authors: Peschle
authors: Ruggero
authors: R
authors: De Maria
mesh_terms: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004900:Erythroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004920:Erythropoiesis / Q000276:immunology*; D053222:Fas Ligand Protein; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D007155:Immunologic Factors / Q000096:biosynthesis / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D000074050:TWEAK Receptor; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006131:Growth Inhibitors; D007155:Immunologic Factors; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C000613297:TNFRSF12A protein, human; C505653:TNFSF10 protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma