Regulation of activation-induced receptor activator of NF-kappaB ligand (RANKL) expression in T cells.
Receptor activator of NF-kappaB ligand (RANKL) is a type II membrane protein of the TNF family and plays a critical role in the regulation of osteoclastogenesis. RANKL expressed on osteoblastic stromal cells has been shown to support osteoclast differentiation originated from hematopoietic precursors. Interestingly, RANKL is also expressed on cells of the immune system including T cells and dendritic cells. We have shown that anti-CD3 could induce RANKL expression in T cell hybridoma A1.1 cells and splenic T cells. RANKL expressed on T cells could effectively induce osteoclast formation from the whole population of murine splenocytes. Furthermore, we have found that the induction of RANKL expression is solely dependent on TCR activation-induced Ca2+ mobilization since its expression can be blocked by cyclosporine A and TMB-8, a Ca2+ mobilization inhibitor. Additionally, treatment of A1.1 cells with ionomycin alone also strongly induces RANKL expression, while phorbol myristate acetate by itself does not. Moreover, although inhibition of c-myc has significant effects on anti-CD3-induced Fas ligand (FasL) expression, we have found that the anti-CD3-induced RANKL expression is independent of c-myc. Surprisingly, in contrast to its inhibitory effect on FasL expression, TGF-beta dramatically increased the expression of anti-CD3-induced RANKL expression. In addition to its potential role in immune responses, RANKL expressed on activated T lymphocytes may provide a mechanism for the communication between the immune and skeletal systems during immune responses and disease states such as rheumatoid arthritis.
Wang
Ruoxiang
R
Department of Immunology, Jerome H. Holland Laboratory, American Red Cross, Rockville, USA.
Zhang
Liying
L
Zhang
Xiaoren
X
Moreno
Jose
J
Celluzzi
Christina
C
Tondravi
Mehrdad
M
Shi
Yufang
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017252:CD3 Complex / Q000502:physiology; D002117:Calcitriol / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D047630:Depsipeptides; D003907:Dexamethasone / Q000494:pharmacology; D053222:Fas Ligand Protein; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006825:Hybridomas / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects; D010456:Peptides, Cyclic; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000502:physiology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D017252:CD3 Complex; D002352:Carrier Proteins; D047630:Depsipeptides; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010456:Peptides, Cyclic; D016271:Proto-Oncogene Proteins c-myc; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011948:Receptors, Antigen, T-Cell; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D016212:Transforming Growth Factor beta; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D003907:Dexamethasone; D016572:Cyclosporine; C087123:romidepsin; D002117:Calcitriol; D013755:Tetradecanoylphorbol Acetate