title: Interleukin-15-activated natural killer cells kill autologous osteoclasts via LFA-1, DNAM-1 and TRAIL, and inhibit osteoclast-mediated bone erosion in vitro.
abstract: Osteoclasts reside on bone and are the main bone resorbing cells playing an important role in bone homeostasis, while natural killer (NK) cells are bone-marrow-derived cells known to play a crucial role in immune defence against viral infections. Although mature NK cells traffic through bone marrow as well as to inflammatory sites associated with enhanced bone erosion, including the joints of patients with rheumatoid arthritis, little is known about the impact NK cells may have on mature osteoclasts and bone erosion. We studied the interaction between human NK cells and autologous monocyte-derived osteoclasts from healthy donors in vitro. We show that osteoclasts express numerous ligands for receptors present on activated NK cells. Co-culture experiments revealed that interleukin-15-activated, but not resting, NK cells trigger osteoclast apoptosis in a dose-dependent manner, resulting in drastically decreased bone erosion. Suppression of bone erosion requires contact between NK cells and osteoclasts, but soluble factors also play a minor role. Antibodies masking leucocyte function-associated antigen-1, DNAX accessory molecule-1 or tumour necrosis factor-related apoptosis-inducing ligand enhance osteoclast survival when co-cultured with activated NK cells and restore the capacity of osteoclasts to erode bone. These results suggest that interleukin-15-activated NK cells may directly affect bone erosion under physiological and pathological conditions.
authors: Department of Cellular Pharmacology, Autoimmune Disease Research, Novo Nordisk A/S, Måløv, Denmark.|Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Shan
authors: S
authors: Feng
authors: Department of Cellular Pharmacology, Autoimmune Disease Research, Novo Nordisk A/S, Måløv, Denmark.
authors: Suzi H
authors: SH
authors: Madsen
authors: Department of Immunopharmacology, Autoimmune Disease Research, Novo Nordisk A/S, Måløv, Denmark.
authors: Natasja N
authors: NN
authors: Viller
authors: Department of Cellular Pharmacology, Autoimmune Disease Research, Novo Nordisk A/S, Måløv, Denmark.|F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, IBD Drug Discovery and Development, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Anita V
authors: AV
authors: Neutzsky-Wulff
authors: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Carsten
authors: C
authors: Geisler
authors: Department of Cellular Pharmacology, Autoimmune Disease Research, Novo Nordisk A/S, Måløv, Denmark.
authors: Lars
authors: L
authors: Karlsson
authors: Department of Cellular Pharmacology, Autoimmune Disease Research, Novo Nordisk A/S, Måløv, Denmark.|Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors: Kalle
authors: K
authors: Söderström
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001862:Bone Resorption / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D019409:Interleukin-15; D016169:Lymphocyte Function-Associated Antigen-1; D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: DNAX accessory molecule-1; leucocyte function-associated antigen-1; natural killer cytotoxicity; osteoclast; tumour necrosis factor-related apoptosis-inducing ligand