IFN-gamma-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL

Eur J Immunol. 2005 Nov;35(11):3353-63. doi: 10.1002/eji.200526141.

Abstract

The current study explored our hypothesis that IFN-gamma-producing human T cells inhibit human osteoclast formation. Activated T cells derived from human PBMC were divided into IFN-gamma-producing T cells (IFN-gamma(+) T cells) and IFN-gamma-non-producing T cells (IFN-gamma(-) T cells). IFN-gamma(+) T cells were cultured with human monocytes in the presence of macrophage-CSF alone. The concentration of soluble receptor activator of NF-kappaB ligand (RANKL) and IFN-gamma, and the amount of membrane type RANKL expressed on T cells, were measured by ELISA. In the patients with early rheumatoid arthritis (RA) treated with non-steroidal anti-inflammatory drugs alone, CD4+ T cells expressing both IFN-gamma and RANKL were detected by flow cytometry. Surprisingly, IFN-gamma(+) T cells, but not IFN-gamma(-) T cells, induced osteoclastogenesis from monocytes, which was completely inhibited by adding osteoprotegerin and increased by adding anti-IFN-gamma antibodies. The levels of both soluble and membrane type RANKL were elevated in IFN-gamma(+) T cells. The ratio of CD4+ T cells expressing both IFN-gamma and RANKL in total CD4+ T cells from PBMC was elevated in RA patients. Contrary to our hypothesis, IFN-gamma(+) human T cells induced osteoclastogenesis through the expression of RANKL, suggesting that Th1 cells play a direct role in bone resorption in Th1 dominant diseases such as RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antirheumatic Agents / pharmacology
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism
  • Bone Resorption / immunology
  • Bone Resorption / metabolism
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Cell Differentiation / immunology*
  • Cell-Free System / immunology
  • Cell-Free System / metabolism
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Humans
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / genetics
  • Interferon-gamma / physiology
  • Macrophage Colony-Stimulating Factor
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology
  • Methotrexate / pharmacology
  • Middle Aged
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Osteoarthritis / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / immunology
  • Osteoclasts / metabolism
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism

Substances

  • Antirheumatic Agents
  • Carrier Proteins
  • Membrane Glycoproteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • TNFSF11 protein, human
  • Macrophage Colony-Stimulating Factor
  • Interferon-gamma
  • Methotrexate