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Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10405-10. Epub 2003 Aug 15.

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

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  • 1Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, GA 30322, USA.

Abstract

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.

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