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Molecular and Cellular Biology, April 2002, p. 2777-2787, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2777-2787.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription

Marcos Vidal,1 Chilakamarti V. Ramana,2 and Adriana S. Dusso1*

Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110,1 Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 441952

Received 6 August 2001/ Returned for modification 21 September 2001/ Accepted 14 January 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.

* Corresponding author. Mailing address: Renal Division, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110. Phone: (314) 362-8243. Fax: (314) 362-8237. E-mail: adusso{at}im.wustl.edu.

Molecular and Cellular Biology, April 2002, p. 2777-2787, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2777-2787.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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