Vitamin D derivatives induce apoptosis and downregulate ICAM-1 levels in peripheral blood mononuclear cells of inflammatory bowel disease patients

• Published in: Inflammatory bowel diseases Vol. 14; no. 5; pp. 597 - 604
• Main Authors: Martinesi, Maria, Treves, Cristina, d'Albasio, Giuseppe, Bagnoli, Siro, Bonanomi, Andrea G., Stio, Maria
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford University Press 01.05.2008; Wiley Subscription Services, Inc., A Wiley Company
• Subjects: 1,25‐dihydroxyvitamin D3; adhesion molecules; Adult; Aged; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Blotting, Western; Calcitriol; Calcitriol - analogs & derivatives; Calcitriol - therapeutic use; Caspase-3; Cell adhesion molecules; Cell interactions; Cell Proliferation - drug effects; Cells, Cultured; DNA - genetics; DNA Fragmentation; Down-Regulation - genetics; Drug development; EB1089; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunosuppressive Agents - therapeutic use; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - blood; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - genetics; infliximab; intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - biosynthesis; Intercellular Adhesion Molecule-1 - drug effects; Intercellular Adhesion Molecule-1 - genetics; Intestine; Leukocyte migration; Leukocytes, Mononuclear - metabolism; Lipopolysaccharides; Lymphocytes; Male; Middle Aged; Monoclonal antibodies; Peripheral blood mononuclear cells; Poly(ADP-ribose) polymerase; Prognosis; Tumor necrosis factor- alpha; Vitamin D; Vitamin D - administration & dosage; Vitamin D - agonists; Vitamin D - analogs & derivatives; Vitamin D - therapeutic use; Vitamins - therapeutic use; Western blotting; apoptosis; EB1089; 1,25-dihydroxyvitamin D; adhesion molecules; infliximab; inflammatory bowel disease
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1002/ibd.20354

BackgroundLymphocytes are crucial in the pathogenesis of inflammatory bowel disease (IBD) and are an important target for drug development. Our aim was to verify whether 2 vitamin D derivatives, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and EB 1089, could induce cell apoptosis and affect cell–cell interaction by regulating adhesion molecule levels.MethodsPeripheral blood mononuclear cell (PBMC) proliferation was studied by [3H]thymidine incorporation and apoptosis was determined using an enzyme-linked immunosorbent assay (ELISA) kit. (Poly(ADP-ribose)polymerase (PARP) cleavage, caspase-3, and ICAM-1 protein levels were determined by Western blot analysis.ResultsOur results indicate that 1,25(OH)2D3 or EB 1089 or anti-TNF-α (infliximab) induce apoptosis in PBMC obtained from healthy subjects. In IBD patients apoptosis is induced by vitamin D derivatives and by anti-TNF-α only in CD patients. Caspase-3 activation and PARP cleavage are registered when PBMC were treated with vitamin D derivatives. ICAM-1 levels remarkably increase when PBMC was incubated with lipopolysaccharide (LPS) or TNF-α. The treatment with the vitamin D derivatives, alone or in combination with LPS or TNF-α, significantly decreases ICAM-1 levels both in healthy subjects and IBD patients. In HUVEC cocultured with PBMC, previously incubated with LPS or TNF-α associated with 1,25(OH)2D3, ICAM-1 levels decrease both in healthy subjects and IBD patients.Conclusions1,25(OH)2D3 and EB 1089 inhibit PBMC proliferation, induce apoptosis in PBMC of healthy subjects and IBD patients, and affect ICAM-1 expression on PBMC and on HUVEC cocultured with PBMC, suggesting that the ICAM-1 downregulation could provide a new target for controlling the recruitment of leukocytes at the sites of inflammation in IBD.