Suppression of IL-8 production in gastric epithelial cells by MUC1 mucin and peroxisome proliferator-associated receptor-

Dept. of Pediatrics, Univ. of Maryland School of Medicine, 655 W. Baltimore St., BRB 13-029, Baltimore, MD 21201. .
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 07/2012; 303(6):G765-74. DOI: 10.1152/ajpgi.00023.2012
Source: PubMed


MUC1 is a membrane-tethered mucin expressed on the apical surface of epithelial cells. Our previous report (Guang W, Ding H, Czinn SJ, Kim KC, Blanchard TG, Lillehoj EP. J Biol Chem 285: 20547-20557, 2010) demonstrated that expression of MUC1 in AGS gastric epithelial cells limits Helicobacter pylori infection and reduces bacterial-driven IL-8 production. In this study, we identified the peroxisome proliferator-associated receptor-γ (PPARγ) upstream of MUC1 in the anti-inflammatory pathway suppressing H. pylori- and phorbol 12-myristate 13-acetate (PMA)-stimulated IL-8 production. Treatment of AGS cells with H. pylori or PMA increased IL-8 levels in cell culture supernatants compared with cells treated with the respective vehicle controls. Prior small interfering (si)RNA-induced MUC1 silencing further increased H. pylori- and PMA-stimulated IL-8 levels compared with a negative control siRNA. MUC1-expressing AGS cells pretreated with the PPARγ agonist troglitazone (TGN) had reduced H. pylori- and PMA-stimulated IL-8 levels compared with cells treated with H. pylori or PMA alone. However, following MUC1 siRNA knockdown, no differences in IL-8 levels were seen between TGN/H. pylori and H. pylori-only cells or between TGN/PMA and PMA-only cells. Finally, TGN-treated AGS cells had increased Muc1 promoter activity, as measured using a Muc1-luciferase reporter gene, and greater MUC1 protein levels by Western blot analysis, compared with vehicle controls. These results support the hypothesis that PPARγ stimulates MUC1 expression by AGS cells, thereby attenuating H. pylori- and PMA-induced IL-8 production.

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    ABSTRACT: More than half of the world's population is infected with Helicobacter pylori, which is strongly linked to the development of chronic gastric inflammation (gastritis), peptic ulcer disease, and stomach cancer. However, for unknown reasons, the vast majority of infected individuals are asymptomatic beyond histologic inflammation. This review article will summarize current knowledge on the molecular mechanisms of H. pylori colonization of the gastric mucosa, with a particular focus on the biochemistry of MUC1 mucin in the host response to bacterial infection.
    No preview · Article · Jul 2012 · Journal of Pediatric Biochemistry
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    Preview · Article · Nov 2013 · Cancer Research
  • Y Hou · J Gao · H Xu · Y Xu · Z Zhang · Q Xu · C Zhang
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    ABSTRACT: MUC1-C oncoprotein is associated with colon, breast, ovarian, lung and pancreatic cancers. MUC1-C interacts with intracellular proteins to elicit signaling cascades that induce cell proliferation and tumor growth. Here we report that peroxisome proliferator-activated receptor gamma (PPARγ), an E3 ubiquitin ligase, is an inhibitor of MUC1-C-mediated cell proliferation. PPARγ does so by binding to and inducing MUC1-C proteasome-dependent degradation that was independent of PPARγ transcriptional activity. Lys134 residue was found to be critically important for PPARγ-mediated MUC1-C degradation, as it terminated MUC1-C-mediated cell proliferation. These findings demonstrate PPARγ induces MUC1-C ubiquitination and degradation that is critical to terminate MUC1-C signaling pathway-elicited cancer.Oncogene advance online publication, 2 December 2013; doi:10.1038/onc.2013.504.
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