AUTHOR=Guang Wei , Twadell William , Lillehoj Erik 

TITLE=Molecular Interactions between MUC1 Epithelial Mucin, β-Catenin, and CagA Proteins

JOURNAL=Frontiers in Immunology

VOLUME=3

YEAR=2012

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2012.00105

DOI=10.3389/fimmu.2012.00105

ISSN=1664-3224

ABSTRACT=<p>Interleukin (IL)-8-driven neutrophil infiltration of the gastric mucosa is pathognomonic of persistent <italic>Helicobacter pylori</italic> infection. Our prior study showed that ectopic over-expression of MUC1 in human AGS gastric epithelial cells reduced <italic>H. pylori</italic>-stimulated IL-8 production compared with cells expressing MUC1 endogenously. Conversely, Muc1 knockout (Muc1<sup>−/−</sup>) mice displayed an increased level of transcripts encoding the keratinocyte chemoattractant (KC), the murine equivalent of human IL-8, in gastric mucosa compared with Muc1<sup>+/+</sup> mice during experimental <italic>H. pylori</italic> infection. The current study tested the hypothesis that a decreased IL-8 level observed following MUC1 over-expression is mediated through the ability of MUC1 to associate with β-catenin, thereby inhibiting <italic>H. pylori</italic>-induced β-catenin nuclear translocation. Increased neutrophil infiltration of the gastric mucosa of <italic>H. pylori</italic>-infected Muc1<sup>−/−</sup> mice was observed compared with Muc1<sup>+/+</sup> wild type littermates, thus defining the functional consequences of increased KC expression in the Muc1-null animals. Protein co-immunoprecipitation (co-IP) studies using lysates of untreated or <italic>H. pylori</italic>-treated AGS cells demonstrated that (a) MUC1 formed a co-IP complex with β-catenin and CagA, (b) MUC1 over-expression reduced CagA/β-catenin co-IP, and (c) in the absence of MUC1 over-expression, <italic>H. pylori</italic> infection increased the nuclear level of β-catenin, (d) whereas MUC1 over-expression decreased bacteria-driven β-catenin nuclear localization. These results suggest that manipulation of MUC1 expression in gastric epithelia may be an effective therapeutic strategy to inhibit <italic>H. pylori</italic>-dependent IL-8 production, neutrophil infiltration, and stomach inflammation.</p>