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Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major
Author(s) -
Ehrchen Jan,
Helming Laura,
Varga Georg,
Pasche Bastian,
Loser Karin,
Gunzer Matthias,
Sunderkötter Cord,
Sorg Clemens,
Roth Johannes,
Lengeling Andreas
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7261com
Subject(s) - calcitriol receptor , arginase , macrophage , in vivo , biology , receptor , immune system , leishmania , leishmania major , nitric oxide , vitamin d and neurology , interferon gamma , immunology , chemistry , in vitro , endocrinology , biochemistry , arginine , parasite hosting , microbiology and biotechnology , amino acid , world wide web , computer science
We have previously reported that 1α,25‐dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) 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 mαjor. 1α,25(OH) 2 D 3 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) 2 D 3 ‐treated macrophages due to Vdr ‐dependent up‐regulation of arginase 1 ex‐pression, 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) 2 D 3 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‐γ by CD4 + and CD8 + T cells. Therefore, we propose that the absence of 1α,25(OH) 2 D 3 ‐mediated inhibition of macrophage microbicidal activity in Vdr‐KO mice results in increased resistance to Leishmania infection.