The Vitamin D analogue TX 527 blocks NF-kappaB activation in peripheral blood mononuclear cells of patients with Crohn's disease

J Steroid Biochem Mol Biol. 2007 Jan;103(1):51-60. doi: 10.1016/j.jsbmb.2006.07.008. Epub 2006 Oct 16.

Abstract

Crohn's disease (CD) is an inflammatory disease characterized by the activation of the immune system in the gut. Since tumor necrosis factor (TNF-alpha) plays an important role in the initiation and perpetuation of intestinal inflammation in CD, we investigated whether TX 527 [19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)], a Vitamin D analogue, could affect peripheral blood mononuclear cells (PBMC) proliferation and exert an immunosuppressive effect on TNF-alpha production in CD patients, and whether this immunosuppressive action could be mediated by NF-kappaB down-regulation. TX 527 significantly decreased cell proliferation and TNF-alpha levels. On activation, NF-kappaB, rapidly released from its cytoplasmatic inhibitor (IKB-alpha), transmigrates into the nucleus and binds to DNA response elements in gene promoter regions. The activation of NF-kappaB, stimulated by TNF-alpha, and its nuclear translocation together with the degradation of IKB-alpha were blocked by TX 527. At the same time, NF-kappaB protein levels present in cytoplasmic extracts decreased in the presence of TNF-alpha and increased when PBMC were incubated with TX 527. The results of our studies indicate that TX 527 inhibits TNF-alpha mediated effects on PBMC and the activation of NF-kappaB and that its action is mediated by Vitamin D receptor (VDR), which is activated when the cells are stimulated with TX 527.

MeSH terms

  • Adult
  • Aged
  • Alkynes / blood*
  • Alkynes / therapeutic use
  • Case-Control Studies
  • Cell Proliferation
  • Cells, Cultured
  • Cholecalciferol / blood*
  • Cholecalciferol / therapeutic use
  • Crohn Disease / blood*
  • Crohn Disease / drug therapy
  • Drug Interactions
  • Female
  • Humans
  • I-kappa B Proteins / blood
  • Immunosuppression
  • Male
  • Middle Aged
  • Molecular Structure
  • NF-kappa B / blood*
  • Receptors, Calcitriol / blood
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vitamin D / analogs & derivatives*
  • Vitamins

Substances

  • Alkynes
  • I-kappa B Proteins
  • NF-kappa B
  • Receptors, Calcitriol
  • Tumor Necrosis Factor-alpha
  • Vitamins
  • inecalcitol
  • Vitamin D
  • Cholecalciferol