Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-γ-induced class II transactivator

作者：Simone Cenci, Gianluca Toraldo, M. Neale Weitzmann, Cristiana Roggia, Yuhao Gao, Wei Qian, Óscar Sierra, Roberto Pacifici · 发表于：Proceedings of the National Academy of Sciences · 年份：2003 · DOI：10.1073/pnas.1533207100 · 被引用次数：316 · 研究领域：Reproductive System and Pregnancy、Estrogen and related hormone effects、Immune Response and Inflammation

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.