Vitamin D regulates claudin-2 and claudin-4 expression in active ulcerative colitis by p- Stat-6 and Smad-7 signaling

Purpose: The tight-junctions (TJ) responsible for the integrity of the intestinal barrier are altered in patients with Inflammatory Bowel Disease (IBD), but the physiopathological mechanisms that lead to this alteration are not yet clear. The aim of the study is to determine whether vitamin D, that regulates the integrity of the epithelial barrier by expressing TJ proteins, reduces claudin-2 (Cl-2) levels by inhibiting Stat-6 phosphorylation, and whether it increases claudin-4 (Cl-4) levels by blocking Smad-7 activity. Methods: Biopsies from inflamed and non-inflamed tracts of terminal ileum and colon from the same patients with active ulcerative colitis (UC) were cultured in the presence or not of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). We used also T84 cells as in vitro model to perform transfection experiments with Stat-6 and Smad-7. Results: The results indicate that 1,25(OH)2D3 reduces Cl-2 levels by blocking Stat-6 phosphorylation and increases Cl- 4 levels by blocking Smad-7 activity in the biopsies obtained from patients with UC. In fact, T84 cells transfected with siRNA of Stat-6 and Smad-7, resulted in reduced Cl-2 levels and increased Cl-4 levels, confirming that 1,25(OH)2D3 regulates Cl-2 and Cl-4 by decreasing levels of p-Stat-6 and Smad-7. Conclusions: Our results indicate that vitamin D mechanism, implicated in regulation of Cl-2 and Cl-4 TJ, is mediated by p-Stat-6 and Smad-7 signal, respectively. The study suggests that vitamin D administration to UC patients could be a useful therapeutic intervention, given that vitamin D deficiency is found in these patients.