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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0678
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 9 3566-3574
Copyright © 2006 by The Endocrine Society

Immune Regulation of 25-Hydroxyvitamin D-1{alpha}-Hydroxylase in Human Monocytic THP1 Cells: Mechanisms of Interferon-{gamma}-Mediated Induction

Lut Overbergh1, Katinka Stoffels1, Mark Waer, Annemieke Verstuyf, Roger Bouillon and Chantal Mathieu

Laboratory for Experimental Medicine and Endocrinology (L.O., K.S., A.V., R.B., C.M.) and Laboratory for Experimental Transplantation (M.W.), University Hospital Gasthuisberg, Catholic University of Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Chantal Mathieu, M.D., Ph.D., LEGENDO, UZ-Gasthuisberg, Onderwijs en Navorsing, Herestraat 49, B-3000 Leuven, Belgium. E-mail: chantal.mathieu{at}med.kuleuven.be.

Context: 25-Hydroxyvitamin D can be activated to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by the rate-limiting enzyme 1{alpha}-hydroxylase in cells of the immune system under control of immune stimuli, such as interferon-{gamma} (IFN{gamma}). In pathological situations, such as sarcoidosis, this can lead to systemic excess of 1,25(OH)2D3 and hypercalcemia.

Objective: The aim of this study was to elucidate the intracellular pathways used by the immune system to tightly regulate 1,25(OH)2D3 production in monocytes and macrophages.

Design: Human monocytic THP1-cells were differentiated and activated by IFN{gamma} and a secondary stimulus, such as lipopolysaccharide or phorbol myristate acetate. 1{alpha}-Hydroxylase mRNA levels were quantified by real-time RT-PCR. The involvement of different signaling pathways in the regulation of this enzyme was investigated using specific pharmacological inhibitors, whereas phosphorylation of signal transducer and activator of transcription 1{alpha} and CCAAT/enhancer binding protein ß was investigated by Western blotting.

Results: In undifferentiated monocytic THP1 cells, IFN{gamma} needs to be combined with a second stimulus, such as lipopolysaccharide, to induce 1{alpha}-hydroxylase. In contrast, in phorbol myristate acetate-differentiated THP1 macrophages, IFN{gamma} alone induces 1{alpha}-hydroxylase and to much higher levels. Many different signaling pathways need to be activated concurrently to allow immune-mediated 1{alpha}-hydroxylase up-regulation. We show involvement of the Janus kinase-signal transducer and activator of transcription, MAPK, and nuclear factor-{kappa}B pathways, with a crucial role for the transcription factor CCAAT/enhancer binding protein ß. Furthermore, histone remodeling involving histone deacetylases and histone acetylase p300 is required.

Conclusion: The present findings indicate that IFN{gamma}-mediated 1,25(OH)2D3 production, as observed in granulomatous diseases such as sarcoidosis, will take place only under conditions where the necessary other signaling pathways are also activated.







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Copyright © 2006 by The Endocrine Society