Developmental expression of a mucinlike glycoprotein (MUCLIN) in pancreas and small intestine of CF mice

1998 ◽  
Vol 275 (2) ◽  
pp. G219-G227 ◽  
Author(s):  
Robert C. De Lisle ◽  
Matthew Petitt ◽  
Kathryn S. Isom ◽  
Donna Ziemer
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Small Intestine ◽  
Morphological Changes ◽  
Developmental Expression ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Pancreatic Acini ◽  
Resultant Increase ◽  
Acinar Lumen

The mucinlike glycoprotein MUCLIN, one of two protein products of the CRP-ductin gene, was used to study changes in the expression of sulfated glycoconjugates during the pathogenesis of cystic fibrosis, using the cystic fibrosis transmembrane conductance regulator (CFTR) knockout mouse (CF mouse). We assessed the appearance of dilated lumina containing protein or mucus plugs in pancreatic acini and crypts of the small intestine and quantified MUCLIN protein and CRP-ductin mRNA during postnatal development. In CF mice, the pancreatic acinar lumen was dilated by postnatal day 16( P16), but MUCLIN protein was first significantly increased by P23 and remained elevated through adulthood compared with normal mice. Similarly, intestinal crypts had CF-like mucus plugs by P16, but MUCLIN protein was first elevated by P23 and remained elevated through adulthood compared with normal mice. In both organs, MUCLIN labeling of the luminal surface was increased concomitantly with dilation and protein or mucus plugging but before upregulation of expression. The morphological changes were then followed by upregulation of MUCLIN protein and CRP-ductin mRNA expression. This is the first direct study of CF pathogenesis and the resultant increase in glycoconjugate gene expression. The data are consistent with CF pathogenesis progressing from an initial alteration in protein secretory dynamics (increased luminal MUCLIN and protein/mucus plugs) to an upregulation of glycoprotein/mucin gene expression, which is expected to exacerbate obstruction of the luminal spaces.

scholarly journals IL-6 and IL-8 increase the expression of glycosyltransferases and sulfotransferases involved in the biosynthesis of sialylated and/or sulfated Lewisx epitopes in the human bronchial mucosa

2008 ◽  
Vol 410 (1) ◽  
pp. 213-223 ◽  
Author(s):  
Sophie Groux-Degroote ◽  
Marie-Ange Krzewinski-Recchi ◽  
Aurélie Cazet ◽  
Audrey Vincent ◽  
Sylvain Lehoux ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Early Death ◽  
High Molecular Mass ◽  
Transmembrane Conductance Regulator ◽  
Regulator Gene ◽  
Bronchial Mucosa ◽  
Sialyl Lewisx ◽  
Transmembrane Conductance ◽  
Cf Transmembrane Conductance Regulator

Bronchial mucins from patients suffering from CF (cystic fibrosis) exhibit glycosylation alterations, especially increased amounts of the sialyl-Lewisx (NeuAcα2-3Galβ1-4[Fucα1-3]GlcNAc-R) and 6-sulfo-sialyl-Lewisx (NeuAcα2-3Galβ1-4[Fucα1-3][SO3H-6]GlcNAc-R) terminal structures. These epitopes are preferential receptors for Pseudomonas aeruginosa, the bacteria responsible for the chronicity of airway infection and involved in the morbidity and early death of CF patients. However, these glycosylation changes cannot be directly linked to defects in CFTR (CF transmembrane conductance regulator) gene expression since cells that secrete airway mucins express no or very low amounts of the protein. Several studies have shown that inflammation may affect glycosylation and sulfation of various glycoproteins, including mucins. In the present study, we show that incubation of macroscopically healthy fragments of human bronchial mucosa with IL-6 (interleukin-6) or IL-8 results in a significant increase in the expression of α1,3/4-fucosyltransferases [FUT11 (fucosyltransferase 11 gene) and FUT3], α2-6- and α2,3-sialyltransferases [ST3GAL6 (α2,3-sialyltransferase 6 gene) and ST6GAL2 (α2,6-sialyltransferase 2 gene)] and GlcNAc-6-O-sulfotransferases [CHST4 (carbohydrate sulfotransferase 4 gene) and CHST6] mRNA. In parallel, the amounts of sialyl-Lewisx and 6-sulfo-sialyl-Lewisx epitopes at the periphery of high-molecular-mass proteins, including MUC4, were also increased. In conclusion, our results indicate that IL-6 and -8 may contribute to the increased levels of sialyl-Lewisx and 6-sulfo-sialyl-Lewisx epitopes on human airway mucins from patients with CF.

scholarly journals Intestinal mucins from cystic fibrosis mice show increased fucosylation due to an induced Fucα1-2 glycosyltransferase

2002 ◽  
Vol 367 (3) ◽  
pp. 609-616 ◽  
Author(s):  
Kristina A. THOMSSON ◽  
Marina HINOJOSA-KURTZBERG ◽  
Karin A. AXELSSON ◽  
Steven E. DOMINO ◽  
John B. LOWE ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Small Intestine ◽  
Blood Group ◽  
Northern Blot Analysis ◽  
Fold Increase ◽  
Transmembrane Conductance Regulator ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Cf Transmembrane Conductance Regulator ◽  
Blood Group H

In gene-targeted mouse models for cystic fibrosis (CF), the disease is mainly manifested by mucus obstruction in the intestine. To explore the mucus composition, mucins insoluble and soluble in 6M guanidinium chloride were purified by three rounds of isopycnic ultracentrifugation from the small and large intestines of CF mice (Cftrm1UNC/Cftrm1UNC) and compared with wild-type mice. The amino acid composition was typical of that for mucins and showed increased amounts of the insoluble (2.5-fold increase) and soluble (7-fold increase) mucins in the small intestine of the CF mice compared with wild-type mice. Mucins from the large intestine of both wild-type and CF mice showed a high but constant level of fucosylation. In contrast, the insoluble and soluble mucins of the small intestine in CF mice revealed a large increase in fucose, whereas those of wild-type mice contained only small amounts of fucose. This increased fucosylation was analysed by releasing the O-linked oligosaccharides followed by GC-MS. NMR spectroscopy revealed that the increased fucosylation was due to an increased expression of blood group H epitopes (Fucα1-2Gal-). Northern-blot analysis, using a probe for the murine Fucα1-2 fucosyltransferase (Fut2), showed an up-regulation of this mRNA in the small intestine of the CF mice, suggesting that this enzyme is responsible for the observed increase in blood group H-type glycosylation. The reason for this up-regulation could be a direct or indirect effect of a non-functional CF transmembrane conductance regulator (CFTR) caused by the absence of CFTR channel.

scholarly journals Aspirin and Some Other Nonsteroidal Anti-Inflammatory Drugs Inhibit Cystic Fibrosis Transmembrane Conductance Regulator Protein Gene Expression in T-84 Cells

1999 ◽  
Vol 8 (4-5) ◽  
pp. 219-227 ◽  
Author(s):  
Danielle Tondelier ◽  
Franck Brouillard ◽  
Joanna Lipecka ◽  
Régis Labarthe ◽  
Moëz Bali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Clinical Manifestations ◽  
Cftr Gene ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Cystic fibrosis (CF) is caused by mutations in the CF gene, which encodes CF transmembrane conductance regulator protein (CFTR), a transmembrane protein that acts as a cAMP-regulated chloride channel. The disease is characterized by inflammation but the relationship between inflammation, abnormal transepithelial ion transport, and the clinical manifestations of CF are uncertain. The present study was undertaken to determine whether three nonsteroidal anti-inflammatory drugs (NSAIDs) (aspirin, ibuprofen, and indomethacin) modulate CFTR gene expression in T-84 cells. Treatment with NSAIDs reduced CFTR transcripts, and decreased cAMP-stimulated anion fluxes, an index of CFTR function. However, the two phenomena occurred at different concentrations of both drugs. The results indicate that NSAIDs can regulate both CFTR gene expression and the function of CFTR-related chloride transport, and suggest that NSAIDs act via multiple transduction pathways.

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