Vidal Marcos, Ramana Chilakamarti V, Dusso Adriana S
Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Mol Cell Biol. 2002 Apr;22(8):2777-87. doi: 10.1128/MCB.22.8.2777-2787.2002.
The cytokine gamma interferon (IFN-gamma) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-gamma induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-gamma-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-gamma and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-gamma action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-gamma/Stat1-induced transcription. This novel 1,25D-IFN-gamma cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties.
细胞因子γ干扰素（IFN-γ）和促钙激素1,25-二羟维生素D（1,25D）是巨噬细胞免疫功能的激活剂。在结节病、结核病和几种肉芽肿病中，IFN-γ诱导巨噬细胞合成1,25D，并抑制1,25D对24-羟化酶的诱导作用，24-羟化酶是1,25D失活的关键酶，会导致血清中1,25D水平升高和高钙血症。本研究阐述了人单核细胞-巨噬细胞中IFN-γ与1,25D的相互作用。IFN-γ和1,25D使信号转导和转录激活因子1（Stat1）和维生素D受体（VDR）在细胞核中积累，促进了Stat1与VDR的DNA结合域之间的蛋白质-蛋白质相互作用。这阻止了VDR-视黄醇X受体（RXR）与维生素D反应元件的结合，从而使VDR从其在24-羟化酶启动子上的正常基因组靶点转移，并拮抗该基因的1,25D-VDR反式激活。相反，1,25D增强IFN-γ的作用。Stat1-VDR相互作用通过阻止酪氨酸去磷酸化使Stat1失活，与IFN-γ/Stat1诱导的转录协同作用。这种新的1,25D-IFN-γ相互作用解释了肉芽肿过程中1,25D稳态异常的发病机制，并为1,25D的免疫调节特性提供了新的见解。
