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Chronic Heavy Alcohol Use is Associated with Upregulated Paneth Cell Antimicrobials in Gastric Mucosa.

Ostaff MJ, Schäfer C, Courth L, Stebe SR, Ott G, Stange EF, Wehkamp J - Clin Transl Gastroenterol (2015)

Bottom Line: We examined the effect of heavy alcohol use on gastric and duodenal Paneth-cell-derived and epithelial antimicrobial peptides (AMPs), cytokines, and the Wnt pathway, an important regulator of epithelial regeneration.No significant differences were found for β-defensins and cytokines (interleukins IL1β, IL6, IL8, IL10).This may be linked to Wnt pathway activation, which has an important role in the epithelial regenerative homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Dr Margarete-Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany.

ABSTRACT

Objectives: How alcohol consumption affects the integrity and the defense mechanisms of the mucosa in the upper gastrointestinal tract is largely unknown. We examined the effect of heavy alcohol use on gastric and duodenal Paneth-cell-derived and epithelial antimicrobial peptides (AMPs), cytokines, and the Wnt pathway, an important regulator of epithelial regeneration.

Methods: In 22 patients with heavy alcohol use and 17 control subjects, biopsies from gastric corpus, antrum, and duodenum were examined for messenger RNA (mRNA) of AMPs, cytokines, and Wnt pathway factors using real-time PCR. The expression of the α-defensin HD5 was analyzed immunohistochemically. The effect of alcohol exposure on Wnt signaling and AMP production was also studied in a gastric cell line using mRNA and reporter gene assays.

Results: Heavy alcohol use was associated with increased expression of Paneth cell HD5 and HD6 mRNA in the antrum, where these products are normally absent (HD5 mRNA in controls vs.

Patients: 2100±900 and 365 500±161 600, HD6 mRNA: 320±130 and 58 300±32 600 copies per 10 ng total RNA, means±s.e.m., P value: 0.022 and 0.011). Upregulated HD5 was independent of intestinal metaplasia that was observed in a minority of patients. No significant differences were found for β-defensins and cytokines (interleukins IL1β, IL6, IL8, IL10). In patients, Wnt pathway factors showed a trend toward higher levels. In vitro, ethanol exposure induced the production of HD5 and HD6 and activation of the Wnt pathway.

Conclusions: Alcohol exposure can induce gastric Paneth cell AMP expression. This may be linked to Wnt pathway activation, which has an important role in the epithelial regenerative homeostasis.

No MeSH data available.


Related in: MedlinePlus

mRNA expression of the important Wnt pathway factors TCF4 (a), TCF1 (b), Wnt3 (c), and Axin-2 (d) in the corpus, the antrum, and the duodenum of patients with heavy alcohol use (HAU) and controls. Shown are means and the respective standard error (s.e.m.). The Wnt pathway (e) is characterized by two states of activity and multiple levels of control. In the absence of Wnt ligands, the central intracellular signaling molecule β-catenin undergoes phosphorylation and ubiquitination-dependent proteasomal degradation. Once Wnt ligands bind to their respective receptors, a protein complex that normally mediates the destruction of β-catenin is inhibited. This allows the accumulation and subsequent entry of β-catenin into the nucleus where it cooperates with transcription factors of the Lef/TCF family to promote target gene transcription.
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fig5: mRNA expression of the important Wnt pathway factors TCF4 (a), TCF1 (b), Wnt3 (c), and Axin-2 (d) in the corpus, the antrum, and the duodenum of patients with heavy alcohol use (HAU) and controls. Shown are means and the respective standard error (s.e.m.). The Wnt pathway (e) is characterized by two states of activity and multiple levels of control. In the absence of Wnt ligands, the central intracellular signaling molecule β-catenin undergoes phosphorylation and ubiquitination-dependent proteasomal degradation. Once Wnt ligands bind to their respective receptors, a protein complex that normally mediates the destruction of β-catenin is inhibited. This allows the accumulation and subsequent entry of β-catenin into the nucleus where it cooperates with transcription factors of the Lef/TCF family to promote target gene transcription.

Mentions: Owing to the important role of Wnt signaling in epithelial homeostasis and Paneth cell biology, we analyzed mRNA levels of TCF1, TCF4, Wnt3, and the Wnt target gene Axin-2 in both groups (Figure 5). We found a trend toward increased transcript levels for all four factors, which, however, was not statistically significant.


Chronic Heavy Alcohol Use is Associated with Upregulated Paneth Cell Antimicrobials in Gastric Mucosa.

Ostaff MJ, Schäfer C, Courth L, Stebe SR, Ott G, Stange EF, Wehkamp J - Clin Transl Gastroenterol (2015)

mRNA expression of the important Wnt pathway factors TCF4 (a), TCF1 (b), Wnt3 (c), and Axin-2 (d) in the corpus, the antrum, and the duodenum of patients with heavy alcohol use (HAU) and controls. Shown are means and the respective standard error (s.e.m.). The Wnt pathway (e) is characterized by two states of activity and multiple levels of control. In the absence of Wnt ligands, the central intracellular signaling molecule β-catenin undergoes phosphorylation and ubiquitination-dependent proteasomal degradation. Once Wnt ligands bind to their respective receptors, a protein complex that normally mediates the destruction of β-catenin is inhibited. This allows the accumulation and subsequent entry of β-catenin into the nucleus where it cooperates with transcription factors of the Lef/TCF family to promote target gene transcription.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816256&req=5

fig5: mRNA expression of the important Wnt pathway factors TCF4 (a), TCF1 (b), Wnt3 (c), and Axin-2 (d) in the corpus, the antrum, and the duodenum of patients with heavy alcohol use (HAU) and controls. Shown are means and the respective standard error (s.e.m.). The Wnt pathway (e) is characterized by two states of activity and multiple levels of control. In the absence of Wnt ligands, the central intracellular signaling molecule β-catenin undergoes phosphorylation and ubiquitination-dependent proteasomal degradation. Once Wnt ligands bind to their respective receptors, a protein complex that normally mediates the destruction of β-catenin is inhibited. This allows the accumulation and subsequent entry of β-catenin into the nucleus where it cooperates with transcription factors of the Lef/TCF family to promote target gene transcription.
Mentions: Owing to the important role of Wnt signaling in epithelial homeostasis and Paneth cell biology, we analyzed mRNA levels of TCF1, TCF4, Wnt3, and the Wnt target gene Axin-2 in both groups (Figure 5). We found a trend toward increased transcript levels for all four factors, which, however, was not statistically significant.

Bottom Line: We examined the effect of heavy alcohol use on gastric and duodenal Paneth-cell-derived and epithelial antimicrobial peptides (AMPs), cytokines, and the Wnt pathway, an important regulator of epithelial regeneration.No significant differences were found for β-defensins and cytokines (interleukins IL1β, IL6, IL8, IL10).This may be linked to Wnt pathway activation, which has an important role in the epithelial regenerative homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Dr Margarete-Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany.

ABSTRACT

Objectives: How alcohol consumption affects the integrity and the defense mechanisms of the mucosa in the upper gastrointestinal tract is largely unknown. We examined the effect of heavy alcohol use on gastric and duodenal Paneth-cell-derived and epithelial antimicrobial peptides (AMPs), cytokines, and the Wnt pathway, an important regulator of epithelial regeneration.

Methods: In 22 patients with heavy alcohol use and 17 control subjects, biopsies from gastric corpus, antrum, and duodenum were examined for messenger RNA (mRNA) of AMPs, cytokines, and Wnt pathway factors using real-time PCR. The expression of the α-defensin HD5 was analyzed immunohistochemically. The effect of alcohol exposure on Wnt signaling and AMP production was also studied in a gastric cell line using mRNA and reporter gene assays.

Results: Heavy alcohol use was associated with increased expression of Paneth cell HD5 and HD6 mRNA in the antrum, where these products are normally absent (HD5 mRNA in controls vs.

Patients: 2100±900 and 365 500±161 600, HD6 mRNA: 320±130 and 58 300±32 600 copies per 10 ng total RNA, means±s.e.m., P value: 0.022 and 0.011). Upregulated HD5 was independent of intestinal metaplasia that was observed in a minority of patients. No significant differences were found for β-defensins and cytokines (interleukins IL1β, IL6, IL8, IL10). In patients, Wnt pathway factors showed a trend toward higher levels. In vitro, ethanol exposure induced the production of HD5 and HD6 and activation of the Wnt pathway.

Conclusions: Alcohol exposure can induce gastric Paneth cell AMP expression. This may be linked to Wnt pathway activation, which has an important role in the epithelial regenerative homeostasis.

No MeSH data available.


Related in: MedlinePlus