HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.06-7261comv1 fj.06-7261comv2 21/12/3208    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ehrchen, J. Articles by Lengeling, A. Search for Related Content PubMed PubMed Citation Articles by Ehrchen, J. Articles by Lengeling, A.

Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major

Jan Ehrchen^*,,1, Laura Helming^,1,2, Georg Varga, Bastian Pasche, Karin Loser, Matthias Gunzer, Cord Sunderkötter^*,, Clemens Sorg^*,3, Johannes Roth^* and Andreas Lengeling^,4

^* Institute for Experimental Dermatology, University of Münster, Münster, Germany;

Research Group Infection Genetics, Department of Experimental Mouse Genetics;

Junior Research Group Immunodynamics, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany; and

Department of Dermatology, University of Münster, Münster, Germany

⁴Correspondence: Research Group Infection Genetics, Department of Experimental Mouse Genetics, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany. E-mail: andreas.lengeling{at}helmholtz-hzi.de

We have previously reported that 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) can selectively suppress key functions of interferon-gamma (IFN-) activated macrophages. To further explore this mechanism for its relevance in vivo, we investigated an infection model that crucially depends on the function of IFN- activated macrophages, the infection with the intracellular protozoan Leishmania major. 1,25(OH)₂D₃ treatment of L. major infected macrophages demonstrated a vitamin D receptor (Vdr) dependent inhibition of macrophage killing activity. Further analysis showed that this was a result of decreased production of nitric oxide by 1,25(OH)₂D₃-treated macrophages due to Vdr-dependent up-regulation of arginase 1 expression, which overrides NO production by Nos2. When analyzing the course of infection in vivo, we found that Vdr-knockout (Vdr-KO) mice were more resistant to L. major infection than their wild-type littermates. This result is in agreement with an inhibitory influence of 1,25(OH)₂D₃ on the macrophage mediated host defense. Further investigation showed that Vdr-KO mice developed an unaltered T helper cell type 1 (Th1) response on infection as indicated by normal production of IFN- by CD4⁺ and CD8⁺ T cells. Therefore, we propose that the absence of 1,25(OH)₂D₃-mediated inhibition of macrophage microbicidal activity in Vdr-KO mice results in increased resistance to Leishmania infection.

Key Words: interferon-gamma • host resistance • macrophage • knockout mice • parasite

This article has been cited by other articles:

				D. Bruce, J. P. Whitcomb, A. August, M. A. McDowell, and M. T. Cantorna Elevated non-specific immunity and normal Listeria clearance in young and old vitamin D receptor knockout mice Int. Immunol., February 1, 2009; 21(2): 113 - 122. [Abstract] [Full Text] [PDF]

				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]

				J. M. Ehrchen, J. Roth, K. Roebrock, G. Varga, W. Domschke, R. Newberry, C. Sorg, C. Muller-Tidow, C. Sunderkotter, T. Kucharzik, et al. The Absence of Cutaneous Lymph Nodes Results in a Th2 Response and Increased Susceptibility to Leishmania major Infection in Mice Infect. Immun., September 1, 2008; 76(9): 4241 - 4250. [Abstract] [Full Text] [PDF]