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

Scientific paper - Original scientific paper

• Author: Danka Grčević
• Author: Ivan Krešimir Lukić
• Author: Nataša Kovačić
• Author: Sanja Ivčević
• Author: Vedran Katavić
• Author: Ana Marušić
• Author's institution: University of Zagreb; School of Medicine
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences

Abstract (english)

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.

• Keywords (english): 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
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Accepted version
• Journal title: Clinical and experimental immunology
• Numbering: vol. 146, no. 1, pp. 146-158
• p-ISSN: 0009-9104
• DOI: https://doi.org/10.1111/j.1365-2249.2006.03181.x
• URN:NBN: urn:nbn:hr:105:188126
• Publication: 2006-10
• Document URL: https://doi.org/10.1111/j.1365-2249.2006.03181.x|
• Type of resource: Text
• Access conditions: Open access
• Created on: 2024-03-28 09:40:41