help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dusso, A.S.
Right arrow Articles by Slatopolsky, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dusso, A.S.
Right arrow Articles by Slatopolsky, E.
The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2222-2232
Copyright © 1997 by The Endocrine Society

Experimental Studies

{gamma}-Interferon-Induced Resistance to 1,25-(OH)2 D3 in Human Monocytes and Macrophages: A Mechanism for the Hypercalcemia of Various Granulomatoses1

A.S. Dusso, S. Kamimura, M. Gallieni, M. Zhong, L. Negrea, S. Shapiro and E. Slatopolsky

The Divisions of Nephrology (A.S.D., S.K., M.G., M.Z., L.N., E.S.) and Respiratory and Critical Care (S.S.), Department of Internal Medicine, Washington University Medical Center, St. Louis, Missouri 63110

Address correspondence and requests for reprints to: Adriana Dusso, Ph.D., Renal Division - Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8126, St. Louis, Missouri 63110-1093.

The hypercalcemia of various granulomatoses is caused by endogenous 1,25-dihydroxyvitamin D [1,25-(OH)2D3] overproduction by disease-activated macrophages. The inability of 1,25(OH)2D3 to suppress its synthesis in macrophages contrasts with the tight control of its production in macrophage precursors, peripheral blood monocytes (PBM). We examined whether 1,25(OH)2D3 resistance develops as PBM differentiate to macrophages or with macrophage activation. Normal human pulmonary alveolar macrophages (PAM) are less sensitive to 1,25(OH)2D3 than PBM, despite similar vitamin D receptor content; however, both PBM and PAM respond to exogenous 1,25-(OH)2D3 by inhibiting 1,25(OH)2D3 synthesis and inducing 1,25(OH)2D3 degradation through enhancement of 24-hydroxylase mRNA levels and activity. The human monocytic cell line THP-1 mimics PAM in 1,25(OH)2D3 synthesis and sensitivity to exogenous 1,25(OH)2D3. We utilized THP-1 cells to examine the response to 1,25(OH)2D3 with macrophage activation. Activation of THP-1 cells with {gamma}-interferon ({gamma}-IFN) enhances 1,25(OH)2D3 synthesis 30-fold, blocks 1,25-(OH)2D3 suppression of its synthesis, and reduces by 42.2% 1,25-(OH)2D3 induction of its degradation. The antagonistic effects of {gamma}-IFN are not merely restricted to enzymatic activities. In THP-1 cells and in normal PBM, {gamma}-IFN inhibits 1,25-(OH)2D3 induction of 24-hydroxylase mRNA levels without reducing mRNA stability, suggesting {gamma}-IFN inhibition of 1,25(OH)2D3 transactivating function. These results explain 1,25(OH)2D3 overproduction in granulomatoses and demonstrate potent inhibition by {gamma}-IFN of 1,25(OH)2D3 action in immune cells.




This article has been cited by other articles:


Home page
 Endocr. Rev.Home page
R. Bouillon, G. Carmeliet, L. Verlinden, E. van Etten, A. Verstuyf, H. F. Luderer, L. Lieben, C. Mathieu, and M. Demay
Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice
Endocr. Rev., October 1, 2008; 29(6): 726 - 776.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. Overbergh, K. Stoffels, M. Waer, A. Verstuyf, R. Bouillon, and C. Mathieu
Immune Regulation of 25-Hydroxyvitamin D-1{alpha}-Hydroxylase in Human Monocytic THP1 Cells: Mechanisms of Interferon-{gamma}-Mediated Induction
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3566 - 3574.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Ren, L. Nguyen, S. Wu, C. Encinas, J. S. Adams, and M. Hewison
Alternative Splicing of Vitamin D-24-Hydroxylase: A NOVEL MECHANISM FOR THE REGULATION OF EXTRARENAL 1,25-DIHYDROXYVITAMIN D SYNTHESIS
J. Biol. Chem., May 27, 2005; 280(21): 20604 - 20611.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
K. M. Spach, L. B. Pedersen, F. E. Nashold, T. Kayo, B. S. Yandell, T. A. Prolla, and C. E. Hayes
Gene expression analysis suggests that 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by stimulating inflammatory cell apoptosis
Physiol Genomics, July 8, 2004; 18(2): 141 - 151.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
M. Vidal, C. V. Ramana, and A. S. Dusso
Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription
Mol. Cell. Biol., April 15, 2002; 22(8): 2777 - 2787.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
U. GÖBEL, R. KETTRITZ, W. SCHNEIDER, and F. C. LUFT
The Protean Face of Renal Sarcoidosis
J. Am. Soc. Nephrol., March 1, 2001; 12(3): 616 - 623.
[Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1997 by The Endocrine Society