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.