Muc1 Cell Surface Mucin Attenuates Epithelial Inflammation in Response to a Common Mucosal Pathogen

Guang, Wei; Ding, Hua; Czinn, Steven J.; Kim, K. Chul; Blanchard, Thomas G.; Lillehoj, Erik P.

doi:10.1074/jbc.m110.121319

Cited by 82 publications

(88 citation statements)

References 53 publications

(26 reference statements)

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“…Transfection with MUC1-targeting siRNAs reduced MUC1 protein to undetectable levels (supplemental Fig. S5) as described pre- viously (25). When these same experiments were performed in A549 cells in which MUC1 had been silenced, no differences in bacterial adhesion to NEU1-targeting versus control siRNA-transfected cells (Fig.…”

Section: Neu1mentioning

confidence: 87%

“…Primers for detection of NEU1, NEU2, NEU3, NEU4, and hypoxanthineguanine phosphoribosyltransferase mRNAs were designed using Primer Express 2.0 and are indicated in Table 1. The levels of NEU1, NEU2, NEU3, and NEU4 transcripts were normalized to hypoxanthine-guanine phosphoribosyltransferase transcripts using the 2 Ϫ⌬⌬Ct method (25). Immunoblotting for NEU1, Cathepsin A, and MUC1-Cells were thoroughly rinsed with ice-cold HEPES buffer and lysed with ice-cold 50 mM Tris-HCl, pH 8.0, 1.0% Nonidet P-40, 0.5% SDS, 150 mM NaCl, 0.1 mM phenylmethylsulfonyl fluoride, 5.0 g/ml leupeptin, 1.0 mg/ml pepstatin A, 1.0 mg/ml aprotinin, 1.0 mM vanadate, 1.0 mM sodium fluoride, 10 mM disodium pyrophosphate, 500 M p-nitrophenol, and 1.0 mM phenylarsine oxide as described (26).…”

Section: Cfte29omentioning

confidence: 99%

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NEU1 Sialidase Expressed in Human Airway Epithelia Regulates Epidermal Growth Factor Receptor (EGFR) and MUC1 Protein Signaling

Lillehoj

Hyun

Feng

et al. 2012

Journal of Biological Chemistry

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159

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Background: Airway epithelia express sialoglycoproteins that respond to danger signals and initiate repair programs. Results: NEU1 sialidase desialylates EGFR and MUC1 in airway epithelia to regulate their responsiveness to ligands and adhesiveness to P. aeruginosa. Conclusion: NEU1 provides an additional level of regulation over airway epithelial responsiveness to ligands and pathogens. Significance: The downstream effects of EGFR desialylation require further investigation.

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Section: Neu1mentioning

confidence: 87%

Section: Cfte29omentioning

confidence: 99%

NEU1 Sialidase Expressed in Human Airway Epithelia Regulates Epidermal Growth Factor Receptor (EGFR) and MUC1 Protein Signaling

Lillehoj

Hyun

Feng

et al. 2012

Journal of Biological Chemistry

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159

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“…MUC1 in gastric epithelial cells acted as a releasable decoy receptor against Helicobacter pylori that limited bacterial infection (32) and attenuated H. pylori-driven proinflammatory cytokine release (33,34). In other studies, whereas both MUC1 and MUC16 were expressed in corneal epithelial cells, only MUC16 provided a barrier to bacterial adherence (35).…”

Section: Muc1/muc1 Deficiency Enhances Ros Production and Tnf-a Releamentioning

confidence: 99%

Membrane-Tethered MUC1 Mucin Counter-Regulates the Phagocytic Activity of Macrophages

Kato

Uchino

Lillehoj

et al. 2016

Am J Respir Cell Mol Biol

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MUC1 (MUC in human; Muc in animals) is a transmembrane mucin glycoprotein expressed in mucosal epithelial cells and hematopoietic cells. MUC1 is involved in the resolution of inflammation during airway Pseudomonas aeruginosa (Pa) infection by suppressing Toll-like receptor signaling in airway epithelial cells. Although alveolar macrophages are recognized as critical mediators of cell-mediated immunity against microorganisms inhaled into the airways, the role of MUC1 in regulating their response is unknown. The aims of this study were to determine whether macrophages express MUC1, and, if so, whether MUC1 expression might be associated with macrophage M0/M1/M2 differentiation or phagocytic activity. Human and mouse MUC1/Muc1 expression was drastically up-regulated in classically activated (M1) macrophages compared with nonactivated (M0) and alternatively activated (M2) macrophages. M1 polarization and Pa stimulation each increased MUC1 ectodomain shedding from the macrophage surface in a TNF-a-converting enzyme-dependent manner. MUC1/Muc1 deficiency in M0 macrophages increased adhesion and phagocytosis of Pa and Escherichia coli compared with MUC1/Muc1-expressing cells, and attenuation of phagocytosis by MUC1 was augmented after polarization into M1 macrophages compared with M0 macrophages. Finally, MUC1/Muc1 deficiency in macrophages increased reactive oxygen species production and TNF-a release in response to Pa compared with MUC1/Muc1-sufficient cells. These results indicate that MUC1/Muc1 expression by macrophages is predominantly in the M1 subtype, and that MUC1/Muc1 expression in these cells decreases their phagocytic activity in an antiinflammatory manner.

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“…In the gastric mucosa, IL-10, TGF-␤, and peroxisome proliferator-associated receptor-␥ (PPAR␥) have been identified as anti-inflammatory mediators (49,52). Our published studies using an H. pylori mouse infection model system demonstrated that MUC1, a membrane-tethered mucin glycoprotein, also downregulates inflammatory responses in gastric epithelial cells (18). Other investigators reported that MUC1 expression not only limits H. pylori colonization of the murine gastric mucosa, but also attenuates the associated gastritis (39).…”

mentioning

confidence: 99%

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

Park

Guang

Blanchard

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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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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Muc1 Cell Surface Mucin Attenuates Epithelial Inflammation in Response to a Common Mucosal Pathogen

Abstract: Helicobacter pylori infection of the gastric mucosa causes an active-chronic inflammation that is strongly linked to the development of duodenal and gastric ulcers and stomach cancer.

Cited by 82 publications

References 53 publications

NEU1 Sialidase Expressed in Human Airway Epithelia Regulates Epidermal Growth Factor Receptor (EGFR) and MUC1 Protein Signaling

NEU1 Sialidase Expressed in Human Airway Epithelia Regulates Epidermal Growth Factor Receptor (EGFR) and MUC1 Protein Signaling

Membrane-Tethered MUC1 Mucin Counter-Regulates the Phagocytic Activity of Macrophages

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

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