CD137L- and RANKL-mediated reverse signals inhibit osteoclastogenesis and T lymphocyte proliferation.
Members of the tumor necrosis factor-related family of ligands and receptors appear to be critical regulators of osteoclastogenesis and various cellular responses in T cells. In the present study, we have investigated CD137L and RANKL (receptor activator of nuclear factor (NF)-kappaB ligand)-induced biological responses in osteoclasts and T cells, respectively. Osteoclast-like cells were generated from murine bone marrow in the presence of RANKL and monocyte-macrophage colony-stimulating factor (M-CSF). RAW264.7 cells (murine monocytic cell line) constitutively express CD137L. Ligation of CD137L with anti-CD137L mAb (TKS-1) inhibits RANKL-induced osteoclast formation in a dose-dependent manner. Bone marrow cells expressed CD137L only when induced by treatment with M-CSF. In bone marrow cells, cross-linking of CD137L with anti-CD137L mAb (TKS-1) inhibits M-CSF/RANKL-evoked formation of multi-nucleated osteoclasts. Further we examined RANKL-mediated regulation of T cell proliferation. Both mouse CD4(+) and CD8(+) T cells expressed RANKL following their activation by anti-CD3 Ab and anti-CD137 Ab. Ligation of RANKL with OPG-Fc, the decoy receptor for RANKL, inhibited both mouse CD4(+) and CD8(+) T cell proliferation. From the above results, we suggest that the cellular responses in cell-to-cell interactions between T cells and osteoclasts are regulated through reciprocal regulations of CD137/CD137L and RANK/RANKL interactions.
Senthilkumar
Ramamoorthy
R
Department of Pharmacology, Kyung Hee University, School of Dentistry, Seoul, Republic of Korea.
Lee
Hyeon-Woo
HW
D053330:4-1BB Ligand / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D053245:RANK Ligand / Q000378:metabolism*
D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C505975:Tnfsf9 protein, mouse; D016173:Macrophage Colony-Stimulating Factor