Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation

Nobuyuki Udagawa, Nicole J. Horwood, Jan Elliott, Alan Mackay, Jane Owens, Haruki Okamura, Masashi Kurimoto, Timothy J. Chambers, T. John Martin, Matthew T. Gillespie

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Abstract

We have established by differential display polymerase chain reaction of mRNA that interleukin (IL)-18 is expressed by osteoblastic stromal cells. The stromal cell populations used for comparison differed in their ability to promote osteoclast-like multinucleated cell (OCL) formation. mRNA for IL-18 was found to be expressed in greater abundance in lines that were unable to support OCL formation than in supportive cells. Recombinant IL-18 was found to inhibit OCL formation in cocultures of osteoblasts and hemopoietic cells of spleen or bone marrow origin. IL-18 inhibited OCL formation in the presence of osteoclastogenic agents including 1alpha,25-dihydroxyvitamin D3, prostaglandin E2, parathyroid hormone, IL-1, and IL-11. The inhibitory effect of IL-18 was limited to the early phase of the cocultures, which coincides with proliferation of hemopoietic precursors. IL-18 has been reported to induce interferon-gamma (IFN-gamma) and granulocyte/macrophage colony-stimulating factor (GM-CSF) production in T cells, and both agents also inhibit OCL formation in vitro. Neutralizing antibodies to GM-CSF were able to rescue IL-18 inhibition of OCL formation, whereas neutralizing antibodies to IFN-gamma did not. In cocultures with osteoblasts and spleen cells from IFN-gamma receptor type II-deficient mice, IL-18 was found to inhibit OCL formation, indicating that IL-18 acted independently of IFN-gamma production: IFN-gamma had no effect in these cocultures. Additionally, in cocultures in which spleen cells were derived from receptor-deficient mice and osteoblasts were from wild-type mice and vice versa, we identified that the target cells for IFN-gamma inhibition of OCL formation were the hemopoietic cells. The work provides evidence that IL-18 is expressed by osteoblasts and inhibits OCL formation via GM-CSF production and not via IFN-gamma production.

Original languageEnglish
Pages (from-to)1005-1012
Number of pages8
JournalJournal of Experimental Medicine
Volume185
Issue number6
Publication statusPublished - 17 Mar 1997

Keywords

  • Animals
  • Animals, Newborn
  • Base Sequence
  • Bone Marrow Cells
  • Cell Differentiation/drug effects
  • Coculture Techniques
  • Cytokines/biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology
  • Interferon-gamma/pharmacology
  • Interleukin-11/pharmacology
  • Interleukin-18
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Osteoblasts/cytology
  • Osteoclasts/cytology
  • Polymerase Chain Reaction
  • RNA, Messenger/biosynthesis
  • Receptors, Interferon/deficiency
  • Recombinant Proteins
  • Transcription, Genetic

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