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-inducing Factor) Is Produced
by Osteoblasts and Acts Via Granulocyte/Macrophage
Colony-stimulating Factor and Not Via Interferon- to
Inhibit Osteoclast Formation
By
From the * St. Vincent's Institute of Medical Research and The University of Melbourne, Department
of Medicine, St. Vincent's Hospital, Fitzroy, Victoria 3065, Australia; 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 1 Department of Histopathology,
St. George's Hospital Medical School, London SW17 ORE, United Kingdom; § Department of
Bacteriology, Hyogo College of Medicine, Nishinomiya 663, Japan; and ¶ Fujisaki Institute,
Hayashibara Biochemical Laboratories Incorporated, Okayama 702, Japan
,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-
(IFN-) 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- did not. In cocultures with osteoblasts and spleen cells from IFN- receptor type II-deficient mice, IL-18 was found to inhibit OCL formation, indicating that IL-18 acted independently of IFN- production: IFN- 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- 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-
production.
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