title: Vitamin D attenuates inflammation in CFTR knockdown intestinal epithelial cells but has no effect in cells with intact CFTR.
abstract: The cystic fibrosis (CF) intestine is characterized by chronic inflammation. CF patients are instructed to ingest supplemental vitamin D on a daily basis thereby exposing their intestinal tract to pharmacological amounts of this vitamin. It has been shown that vitamin D exerts intestinal anti-inflammatory properties. We therefore postulate that vitamin D may be beneficial in the management of CF intestinal inflammation by attenuating cellular inflammatory responses. In this study, we investigated the anti-inflammatory effects of the oral form of vitamin D3 (cholecalciferol) and its metabolites, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3, on cytokine-induced inflammatory responses in intestinal epithelial Caco-2/15 cells with intact expression of CF transmembrane conductance regulator (CFTR) and knockdown for CFTR. We show that 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 inhibited p38MAPK phosphorylation and that these effects were not mediated by changes in the expression of MAPK phosphatase-1 (MKP-1). However, 1,25-dihydroxyvitamin D3 exhibited superior anti-inflammatory effects as it furthermore reduced cytokine-induced NF-κB nuclear translocation and interleukin-8 mRNA stability and secretion. Intriguingly, the anti-inflammatory effects of vitamin D metabolites were only observed in CFTR knockdown cells, which may be explained by alterations in its catabolism associated with changes in CYP24A1 expression. These observations were supported in vivo whereby Cftr(-/-) mice fed large amounts of vitamin D3 for 2 mo led to a reduction in the number of eosinophils and apoptotic cells in the duodenal mucosa of females but not males. Altogether, these findings suggest that vitamin D exerts intestinal anti-inflammatory actions under specific circumstances and may thus prove beneficial in CF.
authors.affiliation: Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Morin
authors.affiliation: Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and.
authors.forename: Valérie
authors.initials: V
authors.lastname: Orlando
authors.affiliation: Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and.
authors.forename: Karoline
authors.initials: K
authors.lastname: St-Martin Crites
authors.affiliation: Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and.
authors.forename: Natacha
authors.initials: N
authors.lastname: Patey
authors.affiliation: Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and Department of Nutrition, Université de Montréal, Montréal, Quebec, Canada genevieve.mailhot@umontreal.ca.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Mailhot
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D018938:Caco-2 Cells; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D016328:NF-kappa B; D014815:Vitamins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014807:Vitamin D; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1
keywords: CFTR; cystic fibrosis; inflammation; intestinal epithelial cells; vitamin D