title: 1alpha,25-Dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation.
abstract: 1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3), the activated vitamin D3 hormone, is a key regulator of calcium homeostasis and thereby indispensable for bone metabolism. In addition, 1alpha,25(OH)2D3 is known to mediate predominantly immunosuppressive responses in vitro and in vivo. It has been demonstrated that macrophages can produce 1alpha,25(OH)2D3 on activation with interferon gamma (IFN-gamma), although little is understood about the biologic significance of this response. We show here that 1alpha,25(OH)2D3 can selectively suppress key effector functions of IFN-gamma-activated macrophages. Among these are the suppression of listericidal activity, the inhibition of phagocyte oxidase-mediated oxidative burst, and the suppression of important IFN-gamma-induced genes, including Ccl5, Cxcl10, Cxcl9, Irf2, Fcgr1, Fcgr3, and Tlr2. The deactivation of IFN-gamma-stimulated macrophages is dependent on a functional vitamin D receptor and 1alpha,25(OH)2D3 acts specifically on IFN-gamma-activated macrophages, whereas the steroid has no effects on resting macrophages. Therefore, the 1alpha,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 1alpha,25(OH)2D3 by IFN-gamma-stimulated macrophages might be an important negative feedback mechanism to control innate and inflammatory responses of activated macrophages.
authors.affiliation: Junior Research Group Infection Genetics, German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Helming
authors.forename: Jens
authors.initials: J
authors.lastname: Böse
authors.forename: Jan
authors.initials: J
authors.lastname: Ehrchen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schiebe
authors.forename: Thomas
authors.initials: T
authors.lastname: Frahm
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Michael
authors.initials: M
authors.lastname: Probst-Kepper
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
authors.forename: Andreas
authors.initials: A
authors.lastname: Lengeling
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018167:Receptors, Calcitriol / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018167:Receptors, Calcitriol; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D007371:Interferon-gamma