Abstract
In many clinical situations which cause thymic involution and thereby result in immune deficiency, T cells are the most often affected, leading to a prolonged deficiency of T cells. Since only the thymic-dependent T cell production pathway secures stable regeneration of fully mature T cells, seeking strategies to enhance thymic regeneration should be a key step in developing therapeutic methods for the treatment of these significant clinical problems. This study clearly shows that receptor activator of NF-kappaB ligand (RANKL) stimulates mouse thymic epithelial cell activities including cell proliferation, thymocyte adhesion to thymic epithelial cells, and the expression of cell death regulatory genes favoring cell survival, cell adhesion molecules such as ICAM-1 and VCAM-1, and thymopoietic factors including IL-7. Importantly, RANKL exhibited a significant capability to facilitate thymic regeneration in mice. In addition, this study demonstrates that RANKL acts directly on the thymus to activate thymus regeneration regardless of its potential influences on thymic regeneration through an indirect or systemic effect. In light of this, the present study provides a greater insight into the development of novel therapeutic strategies for effective thymus repopulation using RANKL in the design of therapies for many clinical conditions in which immune reconstitution is required.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Adhesion / drug effects
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Cell Line
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Cell Proliferation / drug effects
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Cyclophosphamide / pharmacology
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Down-Regulation / drug effects
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Epithelial Cells / cytology*
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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In Vitro Techniques
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism
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Interleukin-7 / genetics*
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Interleukin-7 / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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RANK Ligand / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor Activator of Nuclear Factor-kappa B / genetics
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Receptor Activator of Nuclear Factor-kappa B / metabolism
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Regeneration / drug effects
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Thymus Gland / cytology*
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Thymus Gland / drug effects*
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Thymus Gland / physiology
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Up-Regulation / drug effects
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Vascular Cell Adhesion Molecule-1 / genetics
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Vascular Cell Adhesion Molecule-1 / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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Interleukin-7
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RANK Ligand
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RNA, Messenger
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Receptor Activator of Nuclear Factor-kappa B
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Vascular Cell Adhesion Molecule-1
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bcl-2-Associated X Protein
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bcl-X Protein
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Intercellular Adhesion Molecule-1
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Granulocyte-Macrophage Colony-Stimulating Factor
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Cyclophosphamide