TCF-1-mediated Wnt signaling regulates Paneth cell innate immune defense effectors HD-5 and -6: implications for Crohn's disease

2014 ◽  
Vol 307 (5) ◽  
pp. G487-G498 ◽  
Author(s):  
Julia Beisner ◽  
Zora Teltschik ◽  
Maureen J. Ostaff ◽  
Machteld M. Tiemessen ◽  
Frank J. T. Staal ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Wnt Signaling ◽  
Paneth Cell ◽  
Immune Defense ◽  
Barrier Dysfunction ◽  
Mrna Isoforms ◽  
Stem Cell Maintenance ◽  
Small Intestinal

Wnt signaling regulates small intestinal stem cell maintenance and Paneth cell differentiation. In patients with ileal Crohn's disease (CD), a decrease of Paneth cell α-defensins has been observed that is partially caused by impaired TCF-4 and LRP6 function. Here we show reduced expression of the Wnt signaling effector TCF-1 (also known as TCF-7) in patients with ileal CD. Reporter gene assays and in vitro promoter binding analysis revealed that TCF-1 activates α-defensin HD-5 and HD-6 transcription in cooperation with β-catenin and that activation is mediated by three distinct TCF binding sites. EMSA analysis showed binding of TCF-1 to the respective motifs. In ileal CD patients, TCF-1 mRNA expression levels were significantly reduced. Moreover, we found specifically reduced expression of active TCF-1 mRNA isoforms. Tcf-1 knockout mice exhibited reduced cryptdin expression in the jejunum, which was not consistently seen at other small intestinal locations. Our data provide evidence that TCF-1-mediated Wnt signaling is disturbed in small intestinal CD, which might contribute to the observed barrier dysfunction in the disease.

scholarly journals Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn's disease

2008 ◽  
Vol 1 (S1) ◽  
pp. S67-S74 ◽  
Author(s):  
J Wehkamp ◽  
M Koslowski ◽  
G Wang ◽  
E F Stange
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Barrier Dysfunction ◽  
Small Intestinal

scholarly journals A β-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn’s Disease and Control Subjects

2017 ◽  
Vol 24 (1) ◽  
pp. 166-178 ◽  
Author(s):  
John-Peter Ganda Mall ◽  
Maite Casado-Bedmar ◽  
Martin E Winberg ◽  
Robert J Brummer ◽  
Ida Schoultz ◽  
...  
Keyword(s):  
Mast Cell ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Barrier Dysfunction ◽  
Ussing Chambers ◽  
Beneficial Effects ◽  
And Control

Abstract Background Administration of β-glucan has shown immune-enhancing effects. Our aim was to investigate whether β-glucan could attenuate mast cell (MC)-induced hyperpermeability in follicle-associated epithelium (FAE) and villus epithelium (VE) of patients with Crohn’s disease (CD) and in noninflammatory bowel disease (IBD)-controls. Further, we studied mechanisms of β-glucan uptake and effects on MCs in vitro. Methods Segments of FAE and VE from 8 CD patients and 9 controls were mounted in Ussing chambers. Effects of the MC-degranulator compound 48/80 (C48/80) and yeast-derived β-1,3/1,6 glucan on hyperpermeability were investigated. Translocation of β-glucan and colocalization with immune cells were studied by immunofluorescence. Caco-2-cl1- and FAE-cultures were used to investigate β-glucan-uptake using endocytosis inhibitors and HMC-1.1 to study effects on MCs. Results β-glucan significantly attenuated MC-induced paracellular hyperpermeability in CD and controls. Transcellular hyperpermeability was only significantly attenuated in VE. Baseline paracellular permeability was higher in FAE than VE in both groups, P<0.05, and exhibited a more pronounced effect by C48/80 and β-glucan P<0.05. No difference was observed between CD and controls. In vitro studies showed increased passage, P<0.05, of β-glucan through FAE-culture compared to Caco-2-cl1. Passage was mildly attenuated by the inhibitor methyl-β-cyclodextrin. HMC-1.1 experiments showed a trend to decreasing MC-degranulation and levels of TNF-α but not IL-6 by β-glucan. Immunofluorescence revealed more β-glucan-uptake and higher percentage of macrophages and dendritic cells close to β-glucan in VE of CD compared to controls. Conclusions We demonstrated beneficial effects of β-glucan on intestinal barrier function and increased β-glucan-passage through FAE model. Our results provide important and novel knowledge on possible applications of β-glucan in health disorders and diseases characterized by intestinal barrier dysfunction.

S1757 Tcf-1 Mediated Wnt Signaling Influences Intestinal Innate Immune Defense in Crohn's Disease

2010 ◽  
Vol 138 (5) ◽  
pp. S-268
Author(s):  
Julia Beisner ◽  
Maureen J. Koslowski ◽  
Eduard Stange ◽  
Jan Wehkamp
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Wnt Signaling ◽  
Immune Defense ◽  
Innate Immune ◽  
Innate Immune Defense

In vitro evaluation of IL-18 effects in Crohn's disease

2001 ◽  
Vol 120 (5) ◽  
pp. A316-A317
Author(s):  
P MAERTEN ◽  
S COLPAERT ◽  
Z LIU ◽  
K GEBOES ◽  
J CEUPPENS ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
In Vitro Evaluation

P109 SMOKING NEGATIVELY AFFECTS DISEASE COURSE REGARDLESS OF SMOKING AMOUNT AND MAY BE ASSOCIATED WITH PANETH CELL PHENOTYPE IN JAPANESE CROHN’S DISEASE PATIENTS

2018 ◽  
Vol 154 (1) ◽  
pp. S56
Author(s):  
Takeo Naito ◽  
Ta-Chiang Liu ◽  
Yoichi Kakuta ◽  
Rintaro Moroi ◽  
Masatake Kuroha ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Paneth Cell ◽  
Cell Phenotype ◽  
Disease Course

ACTIVATED INTESTINAL MUSCLE CELLS PROMOTE PREADIPOCYTE MIGRATION: A NOVEL MECHANISM OF CREEPING FAT FORMATION IN CROHN’S DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S34-S34
Author(s):  
Ren Mao ◽  
Genevieve Doyon ◽  
Ilyssa Gordon ◽  
Jiannan Li ◽  
Sinan Lin ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Ex Vivo ◽  
Muscularis Propria ◽  
Dominant Factor ◽  
Stricture Formation ◽  
Intestinal Tissue ◽  
Mesenteric Fat

Abstract Background and Aims Creeping fat, the wrapping of mesenteric fat around the bowel wall, is a typical feature of Crohn’s disease, and is associated with stricture formation and bowel obstruction. How creeping fat forms is unknown, and we interrogated potential mechanisms using novel intestinal tissue and cell interaction systems. Methods Tissues from normal, ulcerative colitis, non-strictured and strictured Crohn’s disease intestinal specimens were obtained. Fresh and decellularized tissue, mesenteric fat explants, primary human adipocytes, pre-adipocytes, muscularis propria cells, and native extracellular matrix were used in multiple ex vivo and in vitro systems involving cell growth, differentiation and migration, proteomics, and integrin expression. Results Crohn’s disease muscularis propria cells produced an extracellular matrix scaffold which is in direct spatial and functional contact with the immediately overlaid creeping fat. The scaffold contained multiple proteins, but only fibronectin production was singularly upregulated by TGF-b1. The muscle cell-derived matrix triggered migration of pre-adipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5β1 on the pre-adipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularized intestinal tissue extracellular matrix. Conclusion Crohn’s disease creeping fat appears to result from the migration of pre-adipocytes out of mesenteric fat and differentiation into adipocytes in response to an increased production of fibronectin by activated muscularis propria cells. These new mechanistic insights may lead to novel approaches for prevention of creeping fat-associated stricture formation.

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