title: 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.
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.
authors.affiliation: St. Vincent's Institute of Medical Research and The University of Melbourne, Department of Medicine, Victoria, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Udagawa
authors.forename: N J
authors.initials: NJ
authors.lastname: Horwood
authors.forename: J
authors.initials: J
authors.lastname: Elliott
authors.forename: A
authors.initials: A
authors.lastname: Mackay
authors.forename: J
authors.initials: J
authors.lastname: Owens
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: M
authors.initials: M
authors.lastname: Kurimoto
authors.forename: T J
authors.initials: TJ
authors.lastname: Chambers
authors.forename: T J
authors.initials: TJ
authors.lastname: Martin
authors.forename: M T
authors.initials: MT
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D017370:Interleukin-11 / Q000494:pharmacology; D020382:Interleukin-18; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins; D014158:Transcription, Genetic; D000096743:Interferon gamma Receptor
chemical_list: D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D017370:Interleukin-11; D020382:Interleukin-18; D012333:RNA, Messenger; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D000096743:Interferon gamma Receptor