IFN-gamma-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL.
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.
Kotake
Shigeru
S
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. skotake@ior.twmu.ac.jp
Nanke
Yuki
Y
Mogi
Makio
M
Kawamoto
Manabu
M
Furuya
Takefumi
T
Yago
Toru
T
Kobashigawa
Tsuyoshi
T
Togari
Akifumi
A
Kamatani
Naoyuki
N
D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D001862:Bone Resorption / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology*; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008727:Methotrexate / Q000494:pharmacology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D018501:Antirheumatic Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D008727:Methotrexate