title: The Vitamin D analogue TX 527 blocks NF-kappaB activation in peripheral blood mononuclear cells of patients with Crohn's disease.
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.
authors.affiliation: Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy. maria.stio@unifi.it
authors.forename: Maria
authors.initials: M
authors.lastname: Stio
authors.forename: Maria
authors.initials: M
authors.lastname: Martinesi
authors.forename: Sara
authors.initials: S
authors.lastname: Bruni
authors.forename: Cristina
authors.initials: C
authors.lastname: Treves
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
authors.forename: Giuseppe
authors.initials: G
authors.lastname: d'Albasio
authors.forename: Siro
authors.initials: S
authors.lastname: Bagnoli
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Bonanomi
mesh_terms: 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
chemical_list: 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