Identification and immune regulation of 25-hydroxyvitamin D-1-<i>α</i>-hydroxylase in murine macrophages

  • L Overbergh
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and
  • B Decallonne
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and
  • D Valckx
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and
  • A Verstuyf
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and
  • J Depovere
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and
  • J Laureys
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and
  • O Rutgeerts
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and
  • R Saint-Arnaud
    Genetics Unit, Shriners Hospital, McGill University, Montréal, Québec, Canada
  • R Bouillon
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and
  • C Mathieu
    Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Catholic University of Leuven, Leuven, Belgium and

抄録

<jats:title>SUMMARY</jats:title><jats:p>Receptors for 1,25(OH)2vitaminD3 are found in most immune cells and important immunological effects have been described in vitro, reflected by its capacity to prevent autoimmunity and to prolong graft survival. The aim of this study was to examine the presence and nature of the enzyme responsible for final activation of the molecule, 1-α-hydroxylase, in murine macrophages and to analyse its regulation and possible role in the immune system. Peritoneal macrophages from C57Bl/6 mice were incubated with lipopolysaccharide (LPS; 100 μg/ml), interferon-gamma (IFN-γ; 500 U/ml) or a combination of both. By quantitative reverse transcriptase-polymerase chain reaction, using primers based on the murine renal cDNA sequence, low levels of 1-α-hydroxylase mRNA were detected in freshly isolated cells (18 ± 7 × 10−6 copies/β-actin copies). Analysis of the cDNA sequence of the gene revealed identical coding sequences for the macrophage and renal enzymes. mRNA levels rose three-fold with LPS (NS), but a six-fold increase was seen after IFN-γ stimulation (P &lt; 0·05). Combining LPS and IFN-γ did not result in a major additional increase, but addition of cyclosporin A further increased levels 2·5-fold both in IFN-γ- and combination-stimulated cells (P &lt; 0·05). Time course analysis revealed that up-regulation of 1-α-hydroxylase was a late phenomenon, preceded by the up-regulation of activating macrophage products such as IL-1 and tumour necrosis factor-alpha. Finally, a defect in 1-α-hydroxylase up-regulation by immune stimuli was found in autoimmune non-obese diabetic mice. In conclusion, we propose that the up-regulation of 1-α-hydroxylase in activated macrophages, resulting in the synthesis of 1,25(OH)2D3, might be a negative feedback loop in inflammation. A defect in this system might be an additional element in tipping the balance towards autoimmunity.</jats:p>

収録刊行物

被引用文献 (3)*注記

もっと見る

詳細情報

問題の指摘

ページトップへ