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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4351-4358.
Prepublished online as a Blood First Edition Paper on August 23, 2005; DOI 10.1182/blood-2005-03-1029.
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Submitted March 14, 2005
Accepted August 9, 2005
1 ,25-dihydroxyvitamin D3 is a potent suppressor of interferon- mediated macrophage activation
Laura Helming, Jens Bose, Jan Ehrchen, Stefanie Schiebe, Thomas Frahm, Robert Geffers, Michael Probst-Kepper, Rudi Balling, and Andreas Lengeling*
Junior Research Group Infection Genetics, German Research Centre for Biotechnology, Braunschweig, Germany
Institute for Experimental Dermatology, University of Munster, Muenster, Germany
Department of Gene Regulation and Differentiation, German Research Centre for Biotechnology, Braunschweig, Germany
Department of Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
Research Group Mucosal Immunity, German Research Centre for Biotechnology, Braunschweig, Germany
German Research Centre for Biotechnology, Braunschweig, Germany
* Corresponding author; email: lengeling{at}gbf.de.
1 ,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the activated vitamin D3 hormone, is a key regulator of calcium homeostasis and thereby indispensable for bone metabolism. Besides that, 1,25(OH)2D3 is known to mediate predominantly immunosuppressive responses in vitro and in vivo. It has been demonstrated that macrophages can produce 1,25(OH)2D3 upon activation with interferon- (IFN-), although little is understood about the biological significance of this response. We show here that 1,25(OH)2D3 can selectively suppress key effector functions of IFN--activated macrophages. Among these are the suppression of listericidal activity, the inhibition of phagocyte oxidase mediated oxidative burst, and the suppression of important IFN--induced genes including Ccl5, Cxcl10, Cxcl9, Irf2, Fcgr1, Fcgr3 and Tlr2. The deactivation of IFN--stimulated macrophages is dependent on a functional vitamin D receptor and 1,25(OH)2D3 acts specifically on IFN--activated macrophages while the steroid has no effects on resting macrophages. Therefore, the 1,25(OH)2D3 mediated suppression of macrophage functions is distinct from previously described macrophage deactivation mechanisms. In conclusion, our data indicate that the production of 1,25(OH)2D3 by IFN--stimulated macrophages might be an important negative feedback mechanism to control innate and inflammatory responses of activated macrophages.
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