Molecular Interactions between MUC1 Epithelial Mucin, β-Catenin, and CagA Proteins.
FRONTIERS IN IMMUNOLOGY(2012)
Abstract
Interleukin (IL)-8-driven neutrophil infiltration of the gastric mucosa is pathognomonic of persistent Hehcobacter pylon infection. Our prior study showed that ectopic over-expression of MUC1 in human AGS gastric epithelial cells reduced H. pylori-stimulated 1158 production compared with cells expressing MUC1 endogenously. Conversely, Mud knockout (Muc1(-/-)) mice displayed an increased level of transcripts encoding the keratinocyte chemoattractant (KC), the murine equivalent of human 1158, in gastric mucosa compared with Muc1(+/+) mice during experimental H. pylon infection. The current study tested the hypothesis that a decreased 1158 level observed following MUC1 over-expression is mediated through the ability of MUC1 to associate with beta-catenin, thereby inhibiting H. pylori-induced beta-catenin nuclear translocation. Increased neutrophil infiltration of the gastric mucosa of H. pylori-infected Muc1-/- mice was observed compared with Muc1(+/+) wild type littermates, thus defining the functional consequences of increased KC expression in the Mud-null animals. Protein co-immunoprecipitation (co-IP) studies using lysates of untreated or H. pylori-treated AGS cells demonstrated that (a) MUC1 formed a co-IP complex with beta-catenin and CagA, (b) MUC1 over-expression reduced CagA/beta-catenin co-1 IP and (c) in the absence of MUC1 over-expression, H. pylon infection increased the nuclear level of beta-catenin, (d) whereas MUC1 over-expression decreased bacteria-driven beta-catenin nuclear localization. These results suggest that manipulation of MUC1 expression in gastric epithelia may be an effective therapeutic strategy to inhibit H. pylori-dependent IL-8 production, neutrophil infiltration, and stomach inflammation.
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Key words
Helicobacter pylori,stomach,gastric,infection
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