title: TGF-beta 1 and IFN-gamma direct macrophage activation by TNF-alpha to osteoclastic or cytocidal phenotype.
abstract: TNF-related activation-induced cytokine (TRANCE; also called receptor activator of NF-kappaB ligand (RANKL), osteoclast differentiation factor (ODF), osteoprotegerin ligand (OPGL), and TNFSF11) induces the differentiation of progenitors of the mononuclear phagocyte lineage into osteoclasts in the presence of M-CSF. Surprisingly, in view of its potent ability to induce inflammation and activate macrophage cytocidal function, TNF-alpha has also been found to induce osteoclast-like cells in vitro under similar conditions. This raises questions concerning both the nature of osteoclasts and the mechanism of lineage choice in mononuclear phagocytes. We found that, as with TRANCE, the macrophage deactivator TGF-beta(1) strongly promoted TNF-alpha-induced osteoclast-like cell formation from immature bone marrow macrophages. This was abolished by IFN-gamma. However, TRANCE did not share the ability of TNF-alpha to activate NO production or heighten respiratory burst potential by macrophages, or induce inflammation on s.c. injection into mice. This suggests that TGF-beta(1) promotes osteoclast formation not only by inhibiting cytocidal behavior, but also by actively directing TNF-alpha activation of precursors toward osteoclasts. The osteoclast appears to be an equivalent, alternative destiny for precursors to that of cytocidal macrophage, and may represent an activated variant of scavenger macrophage.
authors.affiliation: Department of Experimental Pathology, St. George's Hospital Medical School, London, United Kingdom.
authors.forename: S W
authors.initials: SW
authors.lastname: Fox
authors.forename: K
authors.initials: K
authors.lastname: Fuller
authors.forename: K E
authors.initials: KE
authors.lastname: Bayley
authors.forename: J M
authors.initials: JM
authors.lastname: Lean
authors.forename: T J
authors.initials: TJ
authors.lastname: Chambers
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D001426:Bacterial Proteins; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002352:Carrier Proteins / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D007106:Immune Sera / Q000494:pharmacology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000502:physiology*; D008262:Macrophage Activation / Q000276:immunology*; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology*; D053245:RANK Ligand; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology; D053246:Receptor Activator of Nuclear Factor-kappa B; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D007106:Immune Sera; D008562:Membrane Glycoproteins; C079092:MtrB protein, Bacteria; D053245:RANK Ligand; D016601:RNA-Binding Proteins; D053246:Receptor Activator of Nuclear Factor-kappa B; C508961:Tgfb1 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma