Receptor activator of NF-kappa B ligand and osteoprotegerin regulate proinflammatory cytokine production in mice

J Immunol. 2006 Sep 15;177(6):3799-805. doi: 10.4049/jimmunol.177.6.3799.


Receptor activator of NF-kappaB ligand (RANKL) is a membrane-bound or soluble cytokine essential for osteoclast differentiation, whereas the decoy receptor osteoprotegerin (OPG) masks RANKL activity. In mouse serum, both soluble RANKL and OPG are detectable. We observed that mice injected with LPS showed significantly down-regulated serum RANKL levels, whereas serum OPG levels were up-regulated. However, the roles of RANKL and OPG in innate immunity remain obscure. We found that RANKL pretreatment suppressed production of proinflammatory cytokines in macrophages in response to stimulation by bacteria and their components. Furthermore, such RANKL-induced tolerance in macrophages was inhibited by GM-CSF treatment, which blocks RANKL signaling. RANKL-induced tolerance occurred in the absence of c-Fos, which is essential for osteoclast differentiation. In mice lacking OPG, LPS-induced production of proinflammatory cytokines was reduced, whereas in mice lacking RANKL, it was increased, and lethality following LPS injection was also elevated, suggesting that constitutive activities of RANKL suppress cytokine responsiveness to LPS in vivo. Strikingly, prior administration of RANKL protected mice from LPS-induced death. These data reveal prophylactic potential of RANKL in acute inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Carrier Proteins / blood
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Cytokines / biosynthesis*
  • Glycoproteins / blood
  • Glycoproteins / physiology*
  • Inflammation Mediators / metabolism*
  • Ligands
  • Lipopolysaccharides / administration & dosage
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Membrane Glycoproteins / blood
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear / blood
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Tumor Necrosis Factor / blood
  • Receptors, Tumor Necrosis Factor / physiology*


  • Carrier Proteins
  • Cytokines
  • Glycoproteins
  • Inflammation Mediators
  • Ligands
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf11a protein, mouse
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse