Intestinal inflammation reduces expression of DRA, a transporter responsible for congenital chloride diarrhea

Yang, Hongxu; Jiang, Wen; Furth, Emma E.; Wen, Xiaoming; Katz, Jonathan P.; Sellon, Rance K.; Silberg, Debra G.; Antalis, Toni M.; Schweinfest, Clifford W.; Wu, Gary D.

doi:10.1152/ajpgi.1998.275.6.g1445

Cited by 81 publications

(93 citation statements)

References 36 publications

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“…The IL-8 gene transcription rate was determined by nuclear run-on assay using conditions described previously [33]. Nuclei were isolated by NP-40 lysis and Dounce homogenization [34] from control Caco-2 cells or those treated with sodium butyrate (2.5 mM) for 3 days either in the resting state or after 25 min of stimulation with IL-1␤ (5 ng/mL).…”

Section: Cell Culture Line and Conditionsmentioning

confidence: 99%

High-level expression of IkB-b in the surface epithelium of the colon: in vitro evidence for an immunomodulatory role

Huang

Wen

et al. 1999

Journal of Leukocyte Biology

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The intestinal epithelium is spatially segregated into two compartments, one containing undifferentiated cells in a proliferative state and one with non-proliferative differentiated cells. Although this epithelium can produce many immunemodulating substances, emerging evidence suggests that the differentiated cell compartment is less immune responsive. Indeed, it is the differentiated cellular compartment that represents the interface between the highly antigenic luminal environment and the mucosal immune system. The NF-B/rel family of transcriptional activators play a critical role in regulating the inflammatory response by activating a wide variety of immune-modulating genes. These transcription factors are maintained in an inactive state in the cytoplasmic compartment by interaction with inhibitory proteins of the I B family. In this study we show by immunohistochemistry that I B-␤ is expressed at high levels specifically in the differentiated surface epithelium of the colonic mucosa. Using a naturally occurring compound found in the colon of vertebrates, butyrate, we provide evidence in an intestinal cell line that alteration of I B-␤ expression can modulate the transcriptional activation of the interleukin-8 (IL-8) gene by preventing the nuclear translocation of NF-B proteins. Therefore, the expression of I B-␤ in the differentiated surface epithelium of the colon may help these cells act as an immunological barrier to prevent activation of the mucosal immune system.

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Section: Cell Culture Line and Conditionsmentioning

confidence: 99%

High-level expression of IkB-b in the surface epithelium of the colon: in vitro evidence for an immunomodulatory role

Huang

Wen

et al. 1999

Journal of Leukocyte Biology

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“…In animal models, colitis has been associated with a reduced expression of SLC26A3 and unchanged SLC9A3 (52). Human inflammatory colon tissues may show no change in the expression of SLC26A3 (20).…”

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confidence: 99%

Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis

Lohi

Mäkelä

Pulkkinen

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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In inflamed colonic mucosa, the equilibrium between absorptive and secretory functions for electrolyte and salt transport is disturbed. We compared the expression of three major mediators of the intestinal salt transport between healthy and inflamed colonic mucosa to understand the pathophysiology of diarrhea in inflammatory bowel disease. Expression levels of the cystic fibrosis transmembrane regulator (CFTR) (Cl− channel), SLC26A3 (Cl−/HCO[Formula: see text] exchanger) and SLC9A3 (Na+/H+ exchanger) mRNAs were measured by real-time quantitative RT-PCR in peroperative colonic samples from controls ( n = 4) and patients with ulcerative colitis ( n = 10). Several samples were obtained from each individual. Tissue samples were divided into three subgroups according to their histological degree of inflammation. Expression of CFTR and SLC26A3 proteins were determined by immunohistochemistry and Western blotting from the same samples, respectively. Increased expression of CFTR mRNA was observed in all three groups of affected tissue samples, most pronounced in mildly inflamed colonic mucosa (5-fold increase in expression; P < 0.001). The expression of the CFTR protein was detected from health and inflamed colon tissue. Although the expression of the SLC26A3 mRNA was significantly decreased in severe ulcerative colitis ( P< 0.05), the SLC26A3 protein levels remained unchanged in all groups. The expression of SLC9A3 mRNA was significantly changed between the mild and severe groups. Intestinal inflammation modulates the expression of three major mediators of intestinal salt transport and may contribute to diarrhea in ulcerative colitis both by increasing transepithelial Cl− secretion and by inhibiting the epithelial NaCl absorption.

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“…Also, diarrheal phenotype due to loss of luminal membrane Cl Ϫ /base exchange activity is the predominant feature exhibited by DRA knockout mice but not by PAT-1 knockout mice (42). Furthermore, DRA expression is significantly reduced in animal models of inflammatory and infectious diarrhea and in inflammatory bowel disease patients (4,49). Thus DRA has emerged as a potential novel therapeutic target for diarrheal diseases.…”

Section: /Hmentioning

confidence: 99%

Translational repression of SLC26A3 by miR-494 in intestinal epithelial cells

Anbazhagan

Priyamvada

Kumar

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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[downregulated in adenoma (DRA)] is a Cl Ϫ /HCO 3 Ϫ exchanger involved in electroneutral NaCl absorption in the mammalian intestine. Altered DRA expression levels are associated with infectious and inflammatory diarrheal diseases. Therefore, it is critical to understand the regulation of DRA expression. MicroRNAs (miRNAs) are endogenous, small RNAs that regulate protein expression via blocking the translation and/or promoting mRNA degradation. To investigate potential modulation of DRA expression by miRNA, five different in silico algorithms were used to predict the miRNAs that target DRA. Of these miRNAs, miR-494 was shown to have a highly conserved putative binding site in the DRA 3=-untranslated region (3=-UTR) compared with other DRA-targeting miRNAs in vertebrates. Transfection with pmirGLO dual luciferase vector containing DRA 3=-UTR (pmirGLO-3=-UTR DRA) resulted in a significant decrease in relative luciferase activity compared with empty vector. Cotransfection of the DRA 3=-UTR luciferase vector with a miR-494 mimic further decreased luciferase activity compared with cells transfected with negative control. The transfection of a miR-494 mimic into Caco-2 and T-84 cells significantly increased the expression of miR-494 and concomitantly decreased the DRA protein expression. Mutation of the seed sequences for miR-494 in 3=-UTR of DRA abrogated the effect of miR-494 on 3=-UTR. These data demonstrate a novel regulatory mechanism of DRA expression via miR-494 and indicate that targeting this microRNA may serve to be a potential therapeutic strategy for diarrheal diseases.

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Intestinal inflammation reduces expression of DRA, a transporter responsible for congenital chloride diarrhea

Cited by 81 publications

References 36 publications

High-level expression of IkB-b in the surface epithelium of the colon: in vitro evidence for an immunomodulatory role

High-level expression of IkB-b in the surface epithelium of the colon: in vitro evidence for an immunomodulatory role

Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis

Translational repression of SLC26A3 by miR-494 in intestinal epithelial cells

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