A signal through 4-1BB ligand inhibits receptor for activation of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis by increasing interferon (IFN)-beta production.
We tested whether any intracellular signals are transmitted through 4-1BB/CD137 ligand (4-1BBL), using a 4-1BB-Fc fusion protein and 4-1BB-deficient mice. Immobilized 4-1BB-Fc fusion protein strongly inhibited osteoclastogenesis induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) derived from bone marrow macrophages (BMM). Incubation of BMM with M-CSF increased 4-1BBL mRNA and surface expression of 4-1BBL protein. Cross-linking 4-1BBL with immobilized 4-1BB-Fc also dramatically reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells (MNC) derived from the BMM from 4-1BB-deficient mice, suggesting that the inhibitory effect of immobilized 4-1BB on osteoclastogenesis is due to a signal through 4-1BBL. Reverse signaling by 4-1BB-Fc increased the level of interferon (IFN)-beta in BMM and neutralization of IFN-beta reversed the inhibitory effect of immobilized 4-1BB-Fc. Inhibition of osteoclastogenesis by immobilized 4-1BB-Fc is, therefore, at least in part, due to elevation of the level of the negative regulator, IFN-beta in BMM.
Department of Biological Sciences and Immunomodulation Research Center, University of Ulsan, Ulsan 680-749, Republic of Korea.
Hyun-Hee
HH
Shin
Eun-A
EA
Lee
Soo-Jin
SJ
Kim
Byoung S
BS
Kwon
Hye-Seon
HS
Choi
D053330:4-1BB Ligand; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D053330:4-1BB Ligand; D002352:Carrier Proteins; D007141:Immunoglobulin Fc Fragments; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011993:Recombinant Fusion Proteins; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505974:TNFSF9 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C505975:Tnfsf9 protein, mouse; D048069:Tumor Necrosis Factors; D016899:Interferon-beta; D016173:Macrophage Colony-Stimulating Factor