title: A novel in vivo role for osteoprotegerin ligand in activation of monocyte effector function and inflammatory response.
abstract: Osteoprotegerin Ligand (OPGL) is a member of the tumor necrosis factor ligand superfamily and has been shown to be involved in interactions between T cells and dendritic cells. Its role in monocyte effector function, however, has not been defined. In the present study a role for OPGL in activating monocytes/macrophages has been characterized. OPGL was found to up-regulate receptor activator of NF-kappaB (RANK) receptor expression on monocytes, regulate their effector function by inducing cytokine and chemokine secretion, activate antigen presentation through up-regulation of co-stimulatory molecule expression, and promote survival. This activation is mediated through the MAPK pathway as evidenced by activation of p38 and p42/44 MAPK and up-regulation of BCL-XL protein levels. A physiological role for OPGL in monocyte activation and effector function was tested in a model of lipopolysaccharide-induced endotoxic shock. Administration of receptor activator of NF-kappaB (RANK)-Fc to block OPGL activity in vivo was able to protect mice from death induced by sepsis, indicating a hitherto undescribed role for OPGL in monocyte function and in mediating inflammatory response. This was further tested in an animal model of inflammation-mediated arthritis. Treatment with RANK-Fc significantly ameliorated disease development and attenuated bone destruction. Thus, our study strongly suggests that administration of receptor fusion proteins to specifically block OPGL activity in vivo may result in blocking development of monocyte/macrophage-mediated diseases.
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Dhaya
authors.initials: D
authors.lastname: Seshasayee
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Gribling
authors.forename: Jed
authors.initials: J
authors.lastname: Ross
authors.forename: Nicholas
authors.initials: N
authors.lastname: Van Bruggen
authors.forename: Richard
authors.initials: R
authors.lastname: Carano
authors.forename: Iqbal S
authors.initials: IS
authors.lastname: Grewal
mesh_terms: D000818:Animals; D017209:Apoptosis; D001168:Arthritis / Q000139:chemically induced / Q000000981:diagnostic imaging; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division; D002469:Cell Separation; D002470:Cell Survival; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007249:Inflammation; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D053244:Osteoprotegerin; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D015854:Up-Regulation; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D018925:Chemokines; D016207:Cytokines; D006023:Glycoproteins; D007074:Immunoglobulin G; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D019253:Proto-Oncogene Proteins c-bcl-2; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051020:bcl-X Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases