Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator.
Expansion of the pool of tumor necrosis factor (TNF)-alpha-producing T cells is instrumental for the bone loss induced by estrogen deficiency, but the responsible mechanism is unknown. Here we show that ovariectomy up-regulates IFN-gamma-induced class II transactivator, a multitarget immune modulator, resulting in increased antigen presentation by macrophages, enhanced T cell activation, and prolonged lifespan of active T cells. Up-regulation of class II transactivator derives from increased production of IFN-gamma by T helper 1 cells, resulting from enhanced secretion of IL-12 and IL-18 by macrophages. The resulting T cell expansion and bone loss are prevented in vivo by both blockade of antigen presenting cell-induced T cell activation, and silencing of IFN-gamma receptor signaling. Thus, increased IFN-gamma-induced class II transactivator expression and the resulting enhanced T cell proliferation and lifespan are critical to the bone wasting effect of estrogen deficiency.
Cenci
Simone
S
Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, GA 30322, USA.
Toraldo
Gianluca
G
Weitzmann
M Neale
MN
Roggia
Cristiana
C
Gao
Yuhao
Y
Qian
Wei Ping
WP
Sierra
Oscar
O
Pacifici
Roberto
R
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D004967:Estrogens / Q000172:deficiency*; D007371:Interferon-gamma / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins; D010024:Osteoporosis / Q000209:etiology*; D010052:Ovariectomy; D017471:Receptors, Interferon / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis*; D000096743:Interferon gamma Receptor
D004967:Estrogens; D007371:Interferon-gamma; D009687:Nuclear Proteins; D017471:Receptors, Interferon; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C083728:MHC class II transactivator protein