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- Title
Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major.
- Authors
Ehrchen, Jan; Helming, Laura; Varga, Georg; Pasche, Bastian; Loser, Karin; Gunzer, Matthias; Sunderkötter, Cord; Sorg, Clemens; Roth, Johannes; Lengeling, Andreas
- Abstract
We have previously reported that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) can selectively suppress key functions of interferon-gamma (IFN-γ) 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-γ activated macrophages, the infection with the intracellular protozoan Leishmania major, 1α,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 1α,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 1α,25(OH)2D3 on the macrophage mediated host defense. Further investigation showed that Vdr-KO mice developed an unaltered T helper cell type 1 (Thl) response on infection as indicated by normal production of IFN-γ by CD4+ and CD8+ T cells. Therefore, we propose that the absence of 1α,25(OH)2D3-mediated inhibition of macrophage microbicidal activity in Vdr-KO mice results in increased resistance to Leishmania infection.
- Subjects
VITAMIN D; INFECTION; LEISHMANIA; MACROPHAGES; NITRIC oxide; MICE
- Publication
FASEB Journal, 2007, Vol 21, Issue 12, p3208
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.06-7261com