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Reduced
Cadherin/Catenin Complex Expression in Celiac Disease Can Be Reproduced
In Vitro by Cytokine Stimulation |
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Ian Perry, Chris
Tselepis, Judith Hoyland, Tariq H. Iqbal, D. Scott A. Sanders, Brian T.
Cooper, and Janusz A. Z. Jankowski |
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Institute
for Cancer Studies and Department of Medicine (IP, CT, JAZJ), University
of Birmingham, Birmingham, United Kingdom; Gastroenterology Unit (IP, THI,
BTC), City Hospital, Birmingham, United Kingdom; Department of Histopathology
(DSAS), Queen Elizabeth Hospital, Birmingham, United Kingdom; and Musculoskeletal
Research Group (JH), University of Manchester, Manchester, United Kingdom |
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SUMMARY: Celiac disease
is characterized by a chronic immune response to dietary gluten, in which
T cell responses result in elevated mucosal levels of tumor necrosis factor
(TNF)-[alpha], interleukin (IL)-1, interferon (IFN)-[gamma], and transforming
growth factor (TGF)-[beta], which induce profound mucosal remodeling associated
with increased enterocyte proliferation, apoptosis, and migration. Reduced
intestinal expression of the morphoregulatory cell adhesion molecule E-cadherin,
which forms complexes with [beta]-catenin, can increase enterocyte proliferation
and migration. However, its mechanism of action in gastrointestinal inflammatory
conditions and any involvement in celiac disease is unknown. In this study,
we describe changes in E-cadherin and [beta]-catenin expression in celiac
disease tissue and determine the effect of cytokines on their expression
in an in vitro model. We assessed E-cadherin and [beta]-catenin expression
in intestinal biopsies from 24 patients with celiac disease, 12 patients
with treated celiac disease, and 10 healthy patients by immunohistochemistry,
Western blotting, and confocal microscopy. Using Caco-2 cells, we examined
the effect of TNF-[alpha], IL-1, IFN-[gamma], and TGF-[beta] on E-cadherin
expression. E-cadherin transcription was assessed in both intestinal biopsies
and Caco-2 cells by in situ hybridization and RT-PCR, respectively. A marked
reduction in protein expression of E-cadherin and [beta]-catenin that returns
to normal levels after treatment was observed in celiac disease; this reduction
was associated with reduced levels of E-cadherin mRNA. E-cadherin expression
in Caco-2 cells was significantly reduced after TNF-[alpha], IL-1, and IFN-[gamma]
stimulation. The effect of TNF-[alpha] on E-cadherin expression was maximal
after stimulation for 48 hours and also induced modest reductions in [beta]-catenin
expression. The action of TNF-[alpha] on E-cadherin was reversible and was
shown to act at the transcriptional level. These results demonstrate the
novel findings that E-cadherin and [beta]-catenin expression are reversibly
down-regulated in celiac disease and that such changes in epithelial cadherin/catenin
complexes may be mediated by cytokines acting on cadherin transcription. |
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