Abstract
An understanding of the signaling mechanism(s) that regulate the differential expression of gastric mucin MUC5AC in colonic epithelial cells would contribute significantly to investigations of its role in colonic mucosa infected with the bacterial pathogen Shigella dysenteriae. Here we show that S. dysenteriae-Sinduced expression of interleukin-1β upregulates MUC2 expression and the differential expression of MUC5AC. Differential expression of MUC5AC involves crosstalk between interleukin-1β and Akt, whereby the trefoil factor family peptide TFF3 activates Akt by phosphorylation of EGFR. TFF3 also downregulates E-cadherin expression, causing accumulation of β-catenin in the cytosol. Phosphorylation of GSK-3β (inactivated) by activated Akt inhibits ubiquitylation of β-catenin, leading to its nuclear translocation, which then induces the expression of MUC5AC and cyclin D1. Accumulation of cyclin D1 alters the cell cycle, promoting cell survival and proliferation. Human colon HT29MTX cells, which overexpress MUC5AC, were resistant to adherence and invasion of S. dysenteriae when compared with other mucin-secreting HT29 cell types. Thus, during infection with S. dysenteriae, crosstalk between interleukin-1β and Akt wired by TFF3 induces expression of MUC5AC in colonic epithelial cells. Differentially expressed gastric MUC5AC aids in mucosal clearance of S. dysenteriae, inhibiting adherence and invasion of the pathogen to colonic epithelial cells, which protects the host.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoproteins
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Bacterial Adhesion
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Cadherins / genetics
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Cadherins / metabolism
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Cell Proliferation
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Chromones / pharmacology
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Dysentery, Bacillary / genetics
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Dysentery, Bacillary / immunology*
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Dysentery, Bacillary / metabolism*
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Dysentery, Bacillary / pathology
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ErbB Receptors / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Knockdown Techniques
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HT29 Cells
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Humans
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Immunity, Mucosal
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism*
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / metabolism*
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Intestinal Mucosa / microbiology
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Intestinal Mucosa / pathology
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Models, Biological
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Morpholines / pharmacology
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Mucin 5AC / genetics
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Mucin 5AC / metabolism*
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Mucin-2 / genetics
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Mucin-2 / metabolism
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Peptides / antagonists & inhibitors
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Peptides / genetics
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Peptides / metabolism*
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Phosphorylation
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Shigella dysenteriae* / pathogenicity
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Trefoil Factor-3
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Up-Regulation
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beta Catenin / metabolism
Substances
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Apoproteins
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CTNNB1 protein, human
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Cadherins
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Chromones
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Interleukin-1beta
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MUC2 protein, human
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MUC5AC protein, human
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Morpholines
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Mucin 5AC
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Mucin-2
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Peptides
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RNA, Messenger
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TFF3 protein, human
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Trefoil Factor-3
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beta Catenin
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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ErbB Receptors
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Glycogen Synthase Kinase 3