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IL-12, like IL-18, was shown to potently inhibit osteoclast formation in cultures of cocultures of murine osteoblast and spleen cells, as well as in adult spleen cells treated with M-CSF and receptor activator of NF-kappaB ligand (RANKL). Neither IL-12 nor IL-18 was able to inhibit RANKL-induced osteoclast formation in cultured RAW264.7 cells, demonstrating that IL-12, like IL-18, was unable to act directly on osteoclastic precursors. IL-12, like IL-18, was found to act by T cells, since depletion of T cells from the adult spleen cell cultures ablated the inhibitory action of IL-12 and addition of either CD4 or CD8 T cells from C57BL/6 mice to RANKL-stimulated RAW264.7 cultures permitted IL-12 or IL-18 to be inhibitory. Additionally, IL-12 was still able to inhibit osteoclast formation in cocultures with osteoblasts and spleen cells from either GM-CSF R(-/-) mice or IFN-gamma R(-/-) mice, indicating that neither GM-CSF nor IFN-gamma was mediating osteoclast inhibition in these cultures. Combined, IL-18 and IL-12 synergistically inhibited osteoclast formation at concentrations 20- to 1000-fold less, respectively, than when added individually. A candidate inhibitor could not be demonstrated using neutralizing Abs to IL-4, IL-10, or IL-13 or from mRNA expression profiles among known cytokine inhibitors of osteoclastogenesis in response to IL-12 and IL-18 treatment, although the unknown inhibitory molecule was determined to be secreted from T cells.

Original publication

DOI

10.4049/jimmunol.166.8.4915

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

04/2001

Volume

166

Pages

4915 - 4921

Addresses

St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.

Keywords

T-Lymphocytes, Cells, Cultured, Cell Line, Osteoclasts, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Growth Inhibitors, Granulocyte-Macrophage Colony-Stimulating Factor, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Receptors, Interferon, Interleukin-12, Interleukin-18, Drug Combinations, Cell Culture Techniques, Coculture Techniques, Cell Differentiation, Down-Regulation, Drug Synergism, Male, Interferon-gamma