The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/3/1005/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 6, March 17, 1997 1005-1012


Articles

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{ddagger}, Jane Owens{ddagger}, Haruki Okamura§, Masashi Kurimoto, Timothy J. Chambers{ddagger}, T. John Martin*, and Matthew T. Gillespie*

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; {ddagger} 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

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{alpha},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.


Address correspondence to Dr. M.T. Gillespie, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia.

M.T. Gillespie is a Research Fellow of the NHMRC Australia and N. Udagawa was a recipient of a C.R. Roper Fellowship from The University of Melbourne.

N. Udagawa and N.J. Horwood contributed equally to this work.

1 Abbreviations used in this paper: 1{alpha},25(OH)2 D3, 1{alpha},25-dihydroxyvitamin D3; {alpha}GM–CSF, neutralizing antibody to GM–CSF; {alpha}IFN-{gamma}, neutralizing antibody to IFN-{gamma}; ddPCR, differential display PCR; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GM–CSF, granulocyte/macrophage colony-stimulating factor; IFN-{gamma} R–/–, IFN-{gamma} receptor type II knockout; IGIF, interferon-{gamma}-inducing factor; OCL, osteoclast-like multinucleated cells; PGE2, prostaglandin E2; PTH, parathyroid hormone; RT, reverse transcription (or transcribed); TRAP, tartrate resistant acid phosphatase.


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