T-cells mediate an inhibitory effect of interleukin-4 on osteoclastogenesis

Danijela Mirosavljevic, Julian M W Quinn, Jan Elliott, Nicole J Horwood, T John Martin, Matthew T Gillespie

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59 Citations (Scopus)


IL-4 is an important cytokine that can influence bone. We identified two distinct actions of IL-4 to inhibit osteoclast formation: one direct on osteoclast progenitors and the second through the production of a novel T-cell surface-associated molecule(s). These data show a new link between the immune system and bone. The Th2 cytokine interleukin (IL)-4 inhibits osteoclast formation in vitro but also acts on other cell types found in bone, including T-cells and macrophages. Because some osteoclastogenesis inhibitors (e.g., IL-12) act indirectly through T-cells, we investigated IL-4 action on osteoclastogenesis in the presence of T-cells. Osteoclast formation from murine spleen cells treated with RANKL and macrophage colony-stimulating factor (M-CSF) was blocked by IL-4 even when spleen cells were depleted of T-cells (Thy 1.2+) and/or B-cells (B220+). Also, IL-4 inhibited osteoclastogenesis in RANKL/M-CSF-stimulated adherent spleen cells, Rag1 -/- (lymphocyte-deficient) spleen cells, and bone marrow macrophages, indicating an action on myelomonocytic cells to block osteoclastogenesis. In contrast, IL-4 did not inhibit osteoclastogenesis in cells from IL-4 receptor null mice (IL-4R -/-). However, when wildtype T-cells were added to IL-4R -/- spleen cell cultures, IL-4 inhibited osteoclast formation, indicating a T-cell-dependent action. Osteoclast formation in RANKL-stimulated RAW 264.7 cells was not inhibited by IL-4 unless T-cells were added to the culture. Separation of RAW 264.7 cells and T-cells by semipermeable membrane ablated this action of IL-4, suggesting the induction of a membrane-associated osteoclastogenesis inhibitor. However, membrane-bound inhibitors thymic shared antigen-1 (TSA-1) and osteoclast inhibitory lectin (OCIL) were not regulated by IL-4. In summary, at least two mechanisms of IL-4 -mediated osteoclastogenesis inhibition exist, including a direct action on myelomonocytic progenitors (from which osteoclasts derive) and an indirect action through T-cells that may involve novel anti-osteoclastic factors.

Original languageEnglish
Pages (from-to)984-993
Number of pages10
JournalJournal of Bone and Mineral Research
Issue number6
Publication statusPublished - 1 Jun 2003


  • Animals
  • Base Sequence
  • Carrier Proteins/pharmacology
  • Cell Line
  • DNA Primers
  • Interleukin-4/deficiency
  • Lymphocyte Depletion
  • Macrophage Colony-Stimulating Factor/pharmacology
  • Male
  • Membrane Glycoproteins/pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoclasts/drug effects
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen/drug effects
  • T-Lymphocytes/drug effects
  • Th2 Cells/immunology

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