Increased Expression of Hypoxia-Inducible Factor 1α in Coeliac Disease

Abstract

Previously, it has been suggested that hypoxiainducible factor (HIF) 1 signaling may play determinative role in the maintenance of the barrier function of the intestinal epithelium in inflammatory bowel disease. Our aim was to depict the alteration of HIF-1␣ and related genes in celiac disease (CD) where the importance of the barrier function is well known. Duodenal biopsy specimens were collected from 16 children with untreated CD, 9 children with treated CD and 10 controls. HIF-1␣, trefoil factor 1 (TFF1), ecto-5-prime nucleotidase (CD73), and multi drug resistance gene 1 (MDR1) mRNA and HIF-1␣ protein expression were determined by real-time PCR and Western blot, respectively. Localization of HIF-1␣ was determined by immunofluorescent staining. We found increased HIF-1␣ and TFF1 mRNA and HIF-1␣ protein expression in the duodenal mucosa of children with untreated CD compared with controls or children with treated CD (p Ͻ 0.05). In untreated CD children, HIF-1␣ staining was present in cytoplasmic and nuclear region of the villous enterocytes. In treated CD mRNA expression of CD73 and MDR1 were increased compared with controls (p Ͻ 0.01 and 0.05, respectively). Our results of increased mucosal HIF-1␣ expression in CD children suggest the contribution of this signaling pathway in the pathomechanism of CD. (Pediatr Res 68: 118-122, 2010)

Hydroxylases as therapeutic targets in inflammatory bowel disease

“…28,36,37 Indeed, conditional knockout of the HIF-1a isoform has revealed a key role for HIF in mediating functional immune responses in macrophages, dendritic cells, T-cells and neutrophils. [38][39][40][41][42] The expression of hypoxia-inducible transcription factors such as HIF in mucosal tissue has been demonstrated to be increased in diseases of the GI tract including celiac disease 43 and IBD. 31 Although most studies support a protective role for HIF activation in inflammatory conditions of the gut, 27,44,45 its activation has also been proposed to be detrimental.…”

Targeting Hypoxia to Augment Mucosal Barrier Function

“…Three mammalian trefoil factors, TFF1, TFF2, TFF3, have been identified and are variably expressed in mucus secreting epithelial tissues with prominent expression throughout the gastrointestinal tract. TFF1 is primarily expressed in the stomach [46] with expression in the intestine associated primarily with inflammation and mucosal damage [47, 48]. TFF2 is expressed in the gastric and Brunner’s glands, while TFF3 is primarily expressed in the intestine and is also referred to as intestinal trefoil factor, or ITF [43, 44].…”

“…In contrast, TFF1 transcript was increased in 16 untreated pediatric subjects with celiac disease compared to 9 adherents to a gluten-free diet. HIF-1α transcript and protein was also measured and found to be increased in the untreated group [48]. …”

Causes and Consequences of Variability in Drug Transporter Activity in Pediatric Drug Therapy

“…In celiac disease, immune system overactivity results in hypoxia‐induced inflammation of the intestine. ABCB1 mRNA expression in the duodenal mucosa was increased in children with treated celiac disease compared to children with untreated disease and healthy control patients (Table ) …”