Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Arthritis / immunology
-
Autoantigens
-
Autoimmune Diseases / immunology
-
Bone Marrow Cells
-
Bone Resorption / immunology*
-
Carrier Proteins / physiology*
-
Cells, Cultured
-
Coculture Techniques
-
Cysteine Endopeptidases / metabolism
-
Glycoproteins / physiology
-
Interferon-gamma / physiology*
-
JNK Mitogen-Activated Protein Kinases*
-
Lymphocyte Activation
-
MAP Kinase Kinase 4
-
Macrophages / cytology
-
Membrane Glycoproteins / physiology*
-
Mice
-
Mice, Inbred C57BL
-
Mitogen-Activated Protein Kinase Kinases / metabolism
-
Multienzyme Complexes / metabolism
-
NF-kappa B / metabolism
-
Osteoclasts / immunology
-
Osteoclasts / physiology*
-
Osteoprotegerin
-
Proteasome Endopeptidase Complex
-
Proteins / metabolism
-
Proteins / physiology
-
RANK Ligand
-
Receptor Activator of Nuclear Factor-kappa B
-
Receptors, Cytoplasmic and Nuclear / physiology
-
Receptors, Tumor Necrosis Factor
-
Signal Transduction*
-
T-Lymphocytes / physiology*
-
TNF Receptor-Associated Factor 6
-
Ubiquitins / metabolism
Substances
-
Autoantigens
-
Carrier Proteins
-
Glycoproteins
-
Ki antigen
-
Membrane Glycoproteins
-
Multienzyme Complexes
-
NF-kappa B
-
Osteoprotegerin
-
Proteins
-
RANK Ligand
-
Receptor Activator of Nuclear Factor-kappa B
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Tumor Necrosis Factor
-
TNF Receptor-Associated Factor 6
-
Tnfrsf11a protein, mouse
-
Tnfrsf11b protein, mouse
-
Tnfsf11 protein, mouse
-
Ubiquitins
-
Interferon-gamma
-
JNK Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase 4
-
Mitogen-Activated Protein Kinase Kinases
-
Cysteine Endopeptidases
-
Proteasome Endopeptidase Complex