Repozitorij Medicinskog fakulteta Sveučilišta u Zagrebu

Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte/macrophage progenitor lineage commitment towards dendritic cell differentiation through down-regulation of receptor activator of nuclear factor-kappaB and c-Fos

Grčević, Danka and Lukić, Ivan Krešimir and Kovačić, Nataša and Ivčević, Sanja and Katavić, Vedran and Marušić, Ana (2006) Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte/macrophage progenitor lineage commitment towards dendritic cell differentiation through down-regulation of receptor activator of nuclear factor-kappaB and c-Fos. Clinical and experimental immunology, 146 (1). pp. 146-158. ISSN 0009-9104 (Print) 1365-2249 (Electronic)

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    English abstract

    Activated T lymphocytes either stimulate or inhibit osteoclastogenesis from haematopoietic progenitors in different experimental models. To address this controversy, we used several modes of T lymphocyte activation in osteoclast differentiation--mitogen-pulse, anti-CD3/CD28 stimulation and in vivo and in vitro alloactivation. Osteoclast-like cells were generated from non-adherent immature haematopoietic monocyte/macrophage progenitors in murine bone-marrow in the presence of receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) and monocyte-macrophage colony-stimulating factor (M-CSF). All modes of in vivo and in vitro T lymphocyte activation and both CD4(+) and CD8(+) subpopulations produced similar inhibitory effects on osteoclastogenesis paralleled by enhanced dendritic cell (DC) differentiation. Osteoclast-inhibitory effect was associated with T lymphocyte activation and not proliferation, and could be replaced by their culture supernatants. The stage of osteoclast differentiation was crucial for the inhibitory action of activated T lymphocytes on osteoclastogenesis, because the suppressive effect was visible only on early osteoclast progenitors but not on committed osteoclasts. Inhibition was associated specifically with increased granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by the mechanism of progenitor commitment toward lineages other than osteoclast because activated T lymphocytes down-regulated RANK, CD115, c-Fos and calcitonin receptor expression, and increased differentiation towards CD11c-positive DC. An activated T lymphocyte inhibitory role in osteoclastogenesis, confirmed in vitro and in vivo, mediated through GM-CSF release, may be used to counteract activated bone resorption mediated by T lymphocyte-derived cytokines in inflammatory and immune disorders. We also demonstrated the importance of alloactivation in osteoclast differentiation and the ability of cyclosporin A to abrogate T lymphocyte inhibition of osteoclastogenesis, thereby confirming the functional link between alloreaction and bone metabolism.

    Item Type: Article
    MeSH: Dendritic Cells - cytology ; Lymphocyte Activation - physiology ; Osteoclasts - cytology - drug effects - metabolism ; T-Lymphocytes - immunology ; Animals ; Cell Differentiation - drug effects - immunology - physiology ; Cyclosporine - pharmacology ; Down-Regulation - immunology ; Female ; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism ; Immunosuppressive Agents - pharmacology ; Lymphocyte Culture Test, Mixed ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Proto-Oncogene Proteins c-fos - metabolism ; RANK Ligand - metabolism ; Receptor Activator of Nuclear Factor-kappa B - metabolism ; Receptor, Macrophage Colony-Stimulating Factor - metabolism ; Receptors, Calcitonin - metabolism
    Divisions: Katedra za fiziologiju i imunologiju
    Katedra za anatomiju i kliničku anatomiju
    Depositing User: Lea Škorić
    Status: Published
    Creators:
    CreatorsEmail
    Grčević, Danka
    Lukić, Ivan Krešimir
    Kovačić, Nataša
    Ivčević, Sanja
    Katavić, Vedran
    Marušić, Ana
    Date: October 2006
    Date Deposited: 27 Dec 2007
    Last Modified: 23 Sep 2011 18:10
    Subjects: /
    Related URLs:
      URI: http://medlib.mef.hr/id/eprint/317

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