The Vitamin D analogue TX 527 blocks NF-kappaB activation in peripheral blood mononuclear cells of patients with Crohn's disease.
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.
Stio
Maria
M
Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy. maria.stio@unifi.it
Martinesi
Maria
M
Bruni
Sara
S
Treves
Cristina
C
Mathieu
Chantal
C
Verstuyf
Annemieke
A
d'Albasio
Giuseppe
G
Bagnoli
Siro
S
Bonanomi
Andrea G
AG
D000328:Adult; D000368:Aged; D000480:Alkynes / Q000097:blood* / Q000627:therapeutic use; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000097:blood* / Q000627:therapeutic use; D003424:Crohn Disease / Q000097:blood* / Q000188:drug therapy; D004347:Drug Interactions; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000097:blood; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D016328:NF-kappa B / Q000097:blood*; D018167:Receptors, Calcitriol / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014807:Vitamin D / Q000031:analogs & derivatives*; D014815:Vitamins
D000480:Alkynes; D020672:I-kappa B Proteins; D016328:NF-kappa B; D018167:Receptors, Calcitriol; D014409:Tumor Necrosis Factor-alpha; D014815:Vitamins; C409043:inecalcitol; D014807:Vitamin D; D002762:Cholecalciferol