Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Feb 1;101(3):595–603. doi: 10.1172/JCI1333

Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor.

N J Horwood 1, N Udagawa 1, J Elliott 1, D Grail 1, H Okamura 1, M Kurimoto 1, A R Dunn 1, T Martin 1, M T Gillespie 1
PMCID: PMC508603  PMID: 9449693

Abstract

IL-18 inhibits osteoclast (OCL) formation in vitro independent of IFN-gamma production, and this was abolished by the addition of neutralizing antibodies to GM-CSF. We now establish that IL-18 was unable to inhibit OCL formation in cocultures using GM-CSF-deficient mice (GM-CSF -/-). Reciprocal cocultures using either wild-type osteoblasts with GM-CSF -/- spleen cells or GM-CSF -/- osteoblasts with wild-type spleen cells were examined. Wild-type spleen cells were required to elicit a response to IL-18 indicating that cells of splenic origin were the IL-18 target. As T cells comprise a large proportion of the spleen cell population, the role of T cells in osteoclastogenesis was examined. Total T cells were removed and repleted in various combinations. Addition of wild-type T cells to a GM-CSF -/- coculture restored IL-18 inhibition of osteoclastogenesis. Major subsets of T cells, CD4+ and CD8+, were also individually depleted. Addition of either CD4+ or CD8+ wild-type T cells restored IL-18 action in a GM-CSF -/- background, while IL-18 was ineffective when either CD4+ or CD8+ GM-CSF -/- T cells were added to a wild-type coculture. These results highlight the involvement of T cells in IL-18-induced OCL inhibition and provide evidence for a new OCL inhibitory pathway whereby IL-18 inhibits OCL formation due to action upon T cells promoting the release of GM-CSF, which in turn acts upon OCL precursors.

Full Text

The Full Text of this article is available as a PDF (233.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abrahamsen B., Bendtzen K., Beck-Nielsen H. Cytokines and T-lymphocyte subsets in healthy post-menopausal women: estrogen retards bone loss without affecting the release of IL-1 or IL-1ra. Bone. 1997 Mar;20(3):251–258. doi: 10.1016/s8756-3282(96)00384-5. [DOI] [PubMed] [Google Scholar]
  2. Buchinsky F. J., Ma Y., Mann G. N., Rucinski B., Bryer H. P., Paynton B. V., Jee W. S., Hendy G. N., Epstein S. Bone mineral metabolism in T lymphocyte-deficient and -replete strains of rat. J Bone Miner Res. 1995 Oct;10(10):1556–1565. doi: 10.1002/jbmr.5650101018. [DOI] [PubMed] [Google Scholar]
  3. Buchinsky F. J., Ma Y., Mann G. N., Rucinski B., Bryer H. P., Romero D. F., Jee W. S., Epstein S. T lymphocytes play a critical role in the development of cyclosporin A-induced osteopenia. Endocrinology. 1996 Jun;137(6):2278–2285. doi: 10.1210/endo.137.6.8641176. [DOI] [PubMed] [Google Scholar]
  4. Chambers T. J., Revell P. A., Fuller K., Athanasou N. A. Resorption of bone by isolated rabbit osteoclasts. J Cell Sci. 1984 Mar;66:383–399. doi: 10.1242/jcs.66.1.383. [DOI] [PubMed] [Google Scholar]
  5. Cline M. J. Histiocytes and histiocytosis. Blood. 1994 Nov 1;84(9):2840–2853. [PubMed] [Google Scholar]
  6. Consolini R., Cini P., Cei B., Bottone E. Thymic dysfunction in histiocytosis-X. Am J Pediatr Hematol Oncol. 1987 Summer;9(2):146–148. doi: 10.1097/00043426-198722000-00007. [DOI] [PubMed] [Google Scholar]
  7. Hustmyer F. G., Walker E., Yu X. P., Girasole G., Sakagami Y., Peacock M., Manolagas S. C. Cytokine production and surface antigen expression by peripheral blood mononuclear cells in postmenopausal osteoporosis. J Bone Miner Res. 1993 Jan;8(1):51–59. doi: 10.1002/jbmr.5650080108. [DOI] [PubMed] [Google Scholar]
  8. John V., Hock J. M., Short L. L., Glasebrook A. L., Galvin R. J. A role for CD8+ T lymphocytes in osteoclast differentiation in vitro. Endocrinology. 1996 Jun;137(6):2457–2463. doi: 10.1210/endo.137.6.8641199. [DOI] [PubMed] [Google Scholar]
  9. Li P., Allen H., Banerjee S., Seshadri T. Characterization of mice deficient in interleukin-1 beta converting enzyme. J Cell Biochem. 1997 Jan;64(1):27–32. doi: 10.1002/(sici)1097-4644(199701)64:1<27::aid-jcb5>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  10. Martin T. J., Ng K. W. Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity. J Cell Biochem. 1994 Nov;56(3):357–366. doi: 10.1002/jcb.240560312. [DOI] [PubMed] [Google Scholar]
  11. Matsumoto S., Tsuji-Takayama K., Aizawa Y., Koide K., Takeuchi M., Ohta T., Kurimoto M. Interleukin-18 activates NF-kappaB in murine T helper type 1 cells. Biochem Biophys Res Commun. 1997 May 19;234(2):454–457. doi: 10.1006/bbrc.1997.6665. [DOI] [PubMed] [Google Scholar]
  12. Metcalf D., Nicola N. A. The clonal proliferation of normal mouse hematopoietic cells: enhancement and suppression by colony-stimulating factor combinations. Blood. 1992 Jun 1;79(11):2861–2866. [PubMed] [Google Scholar]
  13. Micallef M. J., Ohtsuki T., Kohno K., Tanabe F., Ushio S., Namba M., Tanimoto T., Torigoe K., Fujii M., Ikeda M. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. Eur J Immunol. 1996 Jul;26(7):1647–1651. doi: 10.1002/eji.1830260736. [DOI] [PubMed] [Google Scholar]
  14. Movsowitz C., Epstein S., Fallon M., Ismail F., Thomas S. Cyclosporin-A in vivo produces severe osteopenia in the rat: effect of dose and duration of administration. Endocrinology. 1988 Nov;123(5):2571–2577. doi: 10.1210/endo-123-5-2571. [DOI] [PubMed] [Google Scholar]
  15. Okamura H., Tsutsi H., Komatsu T., Yutsudo M., Hakura A., Tanimoto T., Torigoe K., Okura T., Nukada Y., Hattori K. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 1995 Nov 2;378(6552):88–91. doi: 10.1038/378088a0. [DOI] [PubMed] [Google Scholar]
  16. Robb L., Drinkwater C. C., Metcalf D., Li R., Köntgen F., Nicola N. A., Begley C. G. Hematopoietic and lung abnormalities in mice with a null mutation of the common beta subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9565–9569. doi: 10.1073/pnas.92.21.9565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rosen C. J., Usiskin K., Owens M., Barlascini C. O., Belsky M., Adler R. A. T lymphocyte surface antigen markers in osteoporosis. J Bone Miner Res. 1990 Aug;5(8):851–855. doi: 10.1002/jbmr.5650050808. [DOI] [PubMed] [Google Scholar]
  18. Serrano S., Mariñoso M. L., Soriano J. C., Rubiés-Prat J., Aubia J., Coll J., Bosch J., Del Rio L., Vila J., Goday A. Bone remodelling in human immunodeficiency virus-1-infected patients. A histomorphometric study. Bone. 1995 Feb;16(2):185–191. doi: 10.1016/8756-3282(94)00028-x. [DOI] [PubMed] [Google Scholar]
  19. Stanley E., Lieschke G. J., Grail D., Metcalf D., Hodgson G., Gall J. A., Maher D. W., Cebon J., Sinickas V., Dunn A. R. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5592–5596. doi: 10.1073/pnas.91.12.5592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Takahashi N., Akatsu T., Udagawa N., Sasaki T., Yamaguchi A., Moseley J. M., Martin T. J., Suda T. Osteoblastic cells are involved in osteoclast formation. Endocrinology. 1988 Nov;123(5):2600–2602. doi: 10.1210/endo-123-5-2600. [DOI] [PubMed] [Google Scholar]
  21. Udagawa N., Horwood N. J., Elliott J., Mackay A., Owens J., Okamura H., Kurimoto M., Chambers T. J., Martin T. J., Gillespie M. T. 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. J Exp Med. 1997 Mar 17;185(6):1005–1012. doi: 10.1084/jem.185.6.1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Udagawa N., Takahashi N., Akatsu T., Sasaki T., Yamaguchi A., Kodama H., Martin T. J., Suda T. The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology. 1989 Oct;125(4):1805–1813. doi: 10.1210/endo-125-4-1805. [DOI] [PubMed] [Google Scholar]
  23. Ushio S., Namba M., Okura T., Hattori K., Nukada Y., Akita K., Tanabe F., Konishi K., Micallef M., Fujii M. Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol. 1996 Jun 1;156(11):4274–4279. [PubMed] [Google Scholar]
  24. Yoshimoto T., Okamura H., Tagawa Y. I., Iwakura Y., Nakanishi K. Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3948–3953. doi: 10.1073/pnas.94.8.3948. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES