Differenzielle Muzinexpression im Gastrointestinaltrakt
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Under physiological conditions mucins display a tissue specific expression. MUC2, MUC3, MUC5AC and MUC6 are the major mucins in the gastrointestinal tract. In the intestinal tissue MUC2 and MUC3 are the predominant mucins, whereas MUC5AC and MUC6 are the most important mucins in the stomach. Pathophysiological conditions are characterized by an aberrant gene expression. This includes the expression of non-tissue specific mucins as well as a reduced expression of the specific mucins. During inflammation a co-expression of non-tissue specific mucins was observed. Neoplastic transformations are also associated with an aberrant mucin expression. Obviously, an increased expression of non-specific mucins is related with a more favorable prognosis, while a decreased mucin expression is indicative for an increased cellular dedifferentiation and a poor prognosis. This modified mucin expression may result from a modified gene expression as well as from modifications in the posttranscriptional processing. A modified mucin expression reflects pathophysiological conditions and may support the pathohistological diagnosis.Keywords:
Mucin 2
Pathophysiology
Previously it has been found that the MUC2 gene for intestinal type secretory mucin is highly expressed in intraductal papillary mucinous tumors (IPMT), which are characterized by non‐invasive growth and a favorable outcome. In contrast, MUC2 mRNA is rarely expressed in invasive ductal carcinomas (IDC), which have poor outcomes. The gastric type secretory mucin, MUC5AC, is strongly expressed in the surface mucous cells of gastric mucosa. As both MUC2 and MUC5AC mucins share the characteristics of forming highly viscous gels, it is expected that not only MUC2 mucin expression but also MUC5AC mucin expression may be associated with a favorable prognosis in patients with pancreatic tumors. MUC5AC mucin gene expression was examined in 24 cases of IPMT and 38 cases of IDC by in situ hybridization using a digoxigenin‐labeled oligonucleotide. The results were compared with MUC2 mucin gene expression. Neither MUC5AC mRNA nor MUC2 mRNA was detected in normal pancreatic tissues. MUC5AC mRNA was expressed in 20 of 24 cases of IPMT (83%) and in five of 38 cases of IDC (13%). In contrast, MUC2 mRNA was expressed in 14 of 24 cases of IPMT (58%) and in none of the 38 cases of IDC (0%). The expression rates of MUC5AC mRNA and MUC2 mRNA in IPMT were significantly higher than those in IDC ( P < 0.001, respectively). Intraductal papillary mucinous tumors are characterized by three histological types: (i) villous dark cell type; (ii) papillary clear cell type; and (iii) compact cell type. The villous dark cell type generally expressed both MUC5AC + and MUC2 + genes. Alternatively, the papillary clear cell type and the compact cell type usually showed MUC5AC + and MUC2 − expression. Patients with MUC5AC mRNA expression had a significantly better survival prognosis than those with no MUC5AC mRNA expression ( P < 0.005). In conclusion, MUC5AC gene expression occurs in a majority of IPMT cases, even in those with no MUC2 production. MUC5AC expression can be correlated with tumors that demonstrate an expansive growth pattern and lower levels of invasion and metastasis.
Mucin 2
MUC1
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The quantity and quality of mucins are affected in inflammatory bowel disease (IBD) both because of a reduction in the number of goblet cells and a decrease in the number of sugar residues per oligosaccharide side chain. Alteration in the types of mucins and aberrant location may contribute to the underlying pathology by affecting the mucus barrier function or may instead be a response to inflammation. The authors used the periodic acid-Schiff/Alcian blue stain to distinguish neutral and acidic mucins, and used specific antibodies to the mature goblet cell mucin MUC2, MUC2 core antigen, foveolar cell mucin MUC5AC, and gastric trefoil factor (TFF1), to characterize their presence and distribution in colonic tissue sections from patients with IBD.Both core and mature MUC2 were expressed in all colonic goblet cells from patients with ulcerative colitis (UC) and Crohn disease and from healthy controls. MUC5AC and TFF1, which are not normally expressed by colonic tissue, also were expressed in scattered goblet cells, coexpressing with MUC2. In areas of goblet cell depletion, MUC2 was present in cytoplasmic granules of flattened, cuboidal, nongoblet-cell-like surface cells. The staining was more intense and homogenous with the MUC2 core antibody, suggesting expression of relatively immature mucin. Some of these cells also coexpressed MUC5AC but to a lesser extent. These findings are not unique to IBD but were also found in other types of intestinal inflammation.The study confirms earlier observations that MUC2 is the major colonic mucin in IBD. It appears in two forms: mature MUC2 in goblet cells and immature MUC2 especially in secretory granules of cells that are not phenotypically goblet cells. MUC5AC and TFF1 expression in goblet cells is common in IBD and other inflammatory conditions of the colon. These changes may represent a nonspecific repair function of the colon cells to compensate for damage to barrier function.
Inflammatory Bowel Diseases
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We normally live in symbiosis with approximately 10(13) bacteria present in the colon. Among the several mechanisms maintaining the bacteria/host balance, there is limited understanding of the structure, function, and properties of intestinal mucus. We now demonstrate that the mouse colonic mucus consists of two layers extending 150 mum above the epithelial cells. Proteomics revealed that both of these layers have similar protein composition, with the large gel-forming mucin Muc2 as the major structural component. The inner layer is densely packed, firmly attached to the epithelium, and devoid of bacteria. In contrast, the outer layer is movable, has an expanded volume due to proteolytic cleavages of the Muc2 mucin, and is colonized by bacteria. Muc2(-/-) mice have bacteria in direct contact with the epithelial cells and far down in the crypts, explaining the inflammation and cancer development observed in these animals. These findings show that the Muc2 mucin can build a mucus barrier that separates bacteria from the colon epithelia and suggest that defects in this mucus can cause colon inflammation.
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Giardia duodenalis , a cosmopolitan diarrheagenic parasite of the small intestine, leads to post‐infectious irritable bowel syndrome (PI‐IBS) and extraintestinal complications via unclear mechanisms. The effects of Giardia on the protective mucus layers of the intestine are unknown. Objectives C57BL/6 (WT) and Muc2 ‐/‐ mice, human goblet cell line LS174T, and purified human mucin were exposed to Giardia trophozoites or Giardia 's secreted product to assess the effects of Giardia on MUC2 and goblet cell mucins. Results Infected Muc2 ‐/‐ mice had higher parasitic loads and inhibition of weight gain versus WT mice. Goblet cell mucin (stained with PAS/AB and WGA) was depleted in the small intestine and colon of infected WT mice. Bacterial translocation to the liver and spleen was also increased in infected mice. Immunofluorescence staining of MUC2 was reduced in human goblet cells in vitro after exposure to Giardia trophozoites. In addition, a co‐incubation of Giardia 's secreted products with purified human mucin degraded MUC2. Conclusions MUC2 mucin is protective in giardiasis, but Giardia is able to overcome this barrier. While Giardia colonizes the upper small intestine, it induces mucin depletion in goblet cells throughout the small intestine and colon. Mucin depletion and degradation break down the protective mucus barrier, facilitating bacterial translocation. These mechanisms may contribute to PI‐IBS. Supported by HPI NSERC CREATE, NSERC Discovery and Queen Elizabeth II Master's Scholarship
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Giardia
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The aim of this study was to determine the immunoexpression of mucins in jejunal and ileal villous epithelium using six antibodies against MUC1, MUC2, MUC4 MUC5AC, MUC5B and MUC6. The immunohistochemical score for MUC1 has significantly intense staining compared with MUC2 (P=0.008) and the immunohistochemical socre for MUC4 and MUC 6 has significantly intense staining compared with MUC2 (P=0.032) in ileal villous surface. The immunohistochemical score for MUC4 (P=0.008), MUC5AC (P=0.016) and MUC6 (P=0.016) in ileal villous surface has significantly intense staining compared with ileal cryptic surface. The results of this study demonstrated that six mucins gave distinctly different expression patterns throughout the 1 week-old porcine small intestinal tract.
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Mucin 2
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Mucin 2
MUC1
Lawsonia Intracellularis
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Intestinal metaplasia is a well-established premalignant condition of the stomach that is characterized by mucin carbohydrate modifications defined by histochemical methods. The purpose of the present study was to see whether the expression of mucin core proteins was modified in the different types of intestinal metaplasia and to evaluate the putative usefulness of mucins as "molecular markers" in this setting. We used a panel of monoclonal antibodies with well-defined specificities to MUC1, MUC2, MUC5AC, and MUC6 to characterize the expression pattern of mucins. In contrast to normal gastric mucosa, the complete form or type I intestinal metaplasia (n = 20) displayed little or no expression of MUC1, MUC5AC, or MUC6 in the metaplastic cells and strong expression of the intestinal mucin MUC2 in the goblet cells of all cases. The incomplete forms of intestinal metaplasia, type II (n = 25) and type III (n = 16), expressed MUC1 and MUC5AC in every case, both in goblet and in columnar cells. MUC6 was also expressed in 16 cases of type II intestinal metaplasia and in 11 cases of type III intestinal metaplasia. The intestinal mucin MUC2 was expressed in every case of incomplete intestinal metaplasia, mostly in goblet cells. The mucin expression profile in the different types of intestinal metaplasia allows the identification of two patterns: one defined by decreased levels of expression of "gastric" mucins (MUC1, MUC5AC, and MUC6) and expression of MUC2 intestinal mucin, which corresponds to type I intestinal metaplasia, and the other defined by coexpression of "gastric mucins" (MUC1, MUC5AC, and MUC6) together with the MUC2 mucin, encompassing types II and III intestinal metaplasia. Our results challenge the classical sequential pathway of intestinal metaplasia (from type I to type III via a type II intermediate step).
Intestinal metaplasia
Mucin 2
MUC1
Metaplasia
Goblet cell
Intestinal mucosa
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To investigate the expression of MUC6 mucin in gastric carcinomas, we generated a novel monoclonal antibody (MAb CLH5) using an MUC6 synthetic peptide. MAb CLH5 reacted exclusively with the MUC6 peptide and with native and deglycosylated mucin extracts from gastric tissues. MAb CLH5 immunoreactivity was observed in normal gastric mucosa restricted to pyloric glands of the antrum and mucopeptic cells of the neck zone of the body region. In a series of 104 gastric carcinomas, 31 (29.8%) were immunoreactive for MUC6. The expression of MUC6 was not associated with histomorphological type or with clinicopathological features of the carcinomas. Analysis of the co-expression of MUC6 with other secreted mucins (MUC5AC and MUC2) in 20 gastric carcinomas revealed that different mucin core proteins are co-expressed in 55% of the cases. MUC6 was co-expressed and co-localized with MUC5AC in 45% and with MUC2 in 5% of the cases. Expression of MUC2 alone was observed in 25% of the cases. All carcinomas expressing MUC2 mucin in more than 50% of the cells were of the mucinous type according to the WHO classification. The co-expression of mucins was independent of the histomorphological type and stage of the tumors. In conclusion, we observed, using a novel well-characterized MAb, that MUC6 is a good marker of mucopeptic cell differentiation and is expressed in 30% of gastric carcinomas, independent of the clinicopathological features of the cases. Furthermore, we found that co-expression and co-localization of mucins in gastric carcinomas is independent of histomorphology and staging. Finally, we observed that intestinal mucin MUC2 is expressed as the most prominent mucin of the mucins tested in mucinous-type gastric carcinomas.
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MUC2 mucin produced by goblet cells form the colonic mucus bilayer as the first line of innate defense against pathogen invasion by forming a physical barrier between the lumen and the underlying single layer of mucosal epithelial cells. Goblet cells also produce a variety of proteins that are associated with the mucus layer. Of these proteins, FCGBP is of significant interest due to its structural similarities to MUC2 mucin with unknown functions. In this study, we elucidated the putative functions of FCGBP embedded in MUC2 mucin in response to Salmonella enterica adherence and invasion in human colonic goblet cells. We hypothesis that FCGBP is coordinately produced with MUC2 mucin to play an integral role in forming the protective mucus layer in innate host defense. The aims of the study are: 1) to determine if FCGBP alters the structural integrity of the mucus layer and 2) to quantify structural alterations of the mucus layer in S. enterica adherence and invasion of goblet cells. To investigate whether FCGBP impaired mucus barrier functions, two cell types were investigated: Wildtype LS174T (WT) MUC2 mucus‐producing goblet cells and LS174T cells with a missense mutation in FCGBP (FCGBP MS). To determine if FCGBP MS led to loss in barrier function in the mucus layer, S. enterica adherence and invasion, and 0.2, 1, and 2 µM fluorescent bead penetrability inoculated on WT and FCGBP MS monolayers were quantified. MUC2 and FCGBP mRNA and protein expression induced by S. enterica in WT and FCGBP MS goblet cells were analysed by RT‐PCR and Western blotting. Cell killing by S. enterica was determined by LDH assay. S. enterica induced pro‐inflammatory cytokines responses were analyzed by RT‐PCR and human focus 15‐plex cytokine and chemokine array. FCGBP MS cells exhibited significant loss in MUC2 mucus barrier function as quantified by fluorescent beads penetrability further towards the epithelial cell surface temporally as compared to WT cells independent of bead size. Adherence of live S. enterica was significantly increased in FCGBP MS but not WT cells and induced robust MUC2 mRNA expression and mucus secretion in a time‐dependent manner. Similarly, S. enterica elicited high expression of pro‐inflammatory cytokine mRNA and protein release in FCGBP MS as compared to WT cells. FCGBP MS were readily invaded by S. enterica that resulted in increased cell death as compared to WT cells. More S. enterica adhered, invaded, and killed FCGBP MS as compared to WT cells. Fluorescent beads penetrated the mucus layer closer to the cell surface in FCGBP MS cells. In WT goblet cells, FCGBP and MUC2 were coordinately upregulated in response to S. enterica . The concurrent increase in pro‐inflammatory cytokine expression in FCGBP MS cells in response to S. enterica suggests that bacteria directly interacted with the cell surface suggesting an impaired protective mucus layer. The overall trend for increased bacterial invasion, pro‐inflammatory response, and cell death in FCGBP MS demonstrates that FCGBP was critical in providing structural integrity of the mucus layer.
Mucin 2
Goblet cell
Salmonella enterica
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