T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma.
Bone resorption is regulated by the immune system, where T-cell expression of RANKL (receptor activator of nuclear factor (NF)-kappaB ligand), a member of the tumour-necrosis factor family that is essential for osteoclastogenesis, may contribute to pathological conditions, such as autoimmune arthritis. However, whether activated T cells maintain bone homeostasis by counterbalancing the action of RANKL remains unknown. Here we show that T-cell production of interferon (IFN)-gamma strongly suppresses osteoclastogenesis by interfering with the RANKL-RANK signalling pathway. IFN-gamma induces rapid degradation of the RANK adapter protein, TRAF6 (tumour necrosis factor receptor-associated factor 6), which results in strong inhibition of the RANKL-induced activation of the transcription factor NF-kappaB and JNK. This inhibition of osteoclastogenesis is rescued by overexpressing TRAF6 in precursor cells, which indicates that TRAF6 is the target critical for the IFN-gamma action. Furthermore, we provide evidence that the accelerated degradation of TRAF6 requires both its ubiquitination, which is initiated by RANKL, and IFN-gamma-induced activation of the ubiquitin-proteasome system. Our study shows that there is cross-talk between the tumour necrosis factor and IFN families of cytokines, through which IFN-gamma provides a negative link between T-cell activation and bone resorption. Our results may offer a therapeutic approach to treat the inflammation-induced tissue breakdown.
Takayanagi
H
H
Department of Immunology, Faculty of Medicine and Graduate School of Medicine, University of Tokyo, Japan.
Ogasawara
K
K
Hida
S
S
Chiba
T
T
Murata
S
S
Sato
K
K
Takaoka
A
A
Yokochi
T
T
Oda
H
H
Tanaka
K
K
Nakamura
K
K
Taniguchi
T
T
D000818:Animals; D001168:Arthritis / Q000276:immunology; D001324:Autoantigens; D001327:Autoimmune Diseases / Q000276:immunology; D001854:Bone Marrow Cells; D001862:Bone Resorption / Q000276:immunology*; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006023:Glycoproteins / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation; D048670:MAP Kinase Kinase 4; D008264:Macrophages / Q000166:cytology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000276:immunology / Q000502:physiology*; D053244:Osteoprotegerin; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6; D014452:Ubiquitins / Q000378:metabolism
D001324:Autoantigens; D002352:Carrier Proteins; D006023:Glycoproteins; C099558:Ki antigen; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D053244:Osteoprotegerin; D011506:Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014452:Ubiquitins; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex