UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pseudomyxoma peritonei, a syndrome first described by Karl F. Rokitansky in 1842, is an enigmatic, often fatal intra-abdominal disease characterized by dissecting gelatinous ascites and multifocal peritoneal epithelial implants secreting copious globules of extracellular mucin. Although past interest in the syndrome has focused on the questions of the site of origin (appendix versus ovary), mechanisms of peritoneal spread (multicentricity, redistribution phenomenon, or metastasis), and the degree of malignant transformation present (adenoma, borderline tumor, or carcinoma), another important question is the mechanism behind the accumulation of extracellular mucin, the real cause of the disease's morbidity and mortality irrespective of the site of origin, mechanism of peritoneal spread, or transformed status of its epithelium. Taking advantage of the recently cloned human mucin genes, we decided to investigate this question. Our studies revealed that pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells. These cells also express MUC5AC but the latter mucin is not specific for pseudomyxoma peritonei. MUC2 expression accounts for the voluminous deposits of extracellular mucin (mucin:cell ratios exceeding 10:1) and distinguishes pseudomyxoma peritonei secondarily involving the ovary from primary ovarian mucinous tumors with peritoneal implants. Because mucinous tumors of the appendix similarly express MUC2, the MUC2 expression profile also supports an appendiceal rather than ovarian origin for pseudomyxoma peritonei. Increased steady-state mRNA is observed in pooled cases of pseudomyxoma peritonei but does not occur on the basis of gene rearrangement or gene amplification. Primary epithelial cell cultures obtained from pseudomyxoma peritonei express MUC2 whose levels can be epigenetically regulated. These lines up-regulate MUC2 expression in response to both methylation inhibition by 5-azacytidine and exposure to Pseudomonas aeruginosa lipopolysaccharide, both of whose effects can be suppressed by genistein pretreatment. Both immunocytochemical as well as in situ hybridization studies with ancillary digital image analysis reveal that MUC2 expression in cases of pseudomyxoma peritonei is independent of the degrees of malignant transformation that are present and, in fact, reflects the constitutive levels of expression observed in normal goblet cells of the appendix. Extracellular mucin accumulates dramatically in pseudomyxoma peritonei because the number of MUC2-secreting cells dramatically increase and because this MUC2 has no place to drain. These studies suggest that pseudomyxoma peritonei should be regarded as a disease of MUC2-expressing goblet cells whose MUC2 expression might be susceptible to pharmacological targeting.
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PMID:Pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells. 1216 80

Bacterial infection, bile stasis, mucin hypersecretion, and an alteration of the mucin profile such as an aberrant expression of gel-forming apomucin (MUC2 and MUC5AC) in the intrahepatic biliary tree are thought to be important in the lithogenesis of hepatolithiasis. So far, there have been no detailed studies linking bacterial infection to altered mucus secretion of biliary epithelium. In this study, the influence of lipopolysaccharide (LPS), a bacterial component, on apomucin expression in cultured murine biliary epithelial cells was examined with emphasis on the participation of tumor necrosis factor (TNF)-alpha. It was found that LPS up-regulated the expression of MUC2 and MUC5AC in cultured murine biliary epithelial cells. LPS also induced the expression of TNF-alpha in biliary epithelial cells and its secretion into the culture medium. The up-regulation of these apomucins was inhibited by pretreatment with TNF-alpha antibody. TNF-alpha alone also induced the overexpression of MUC2 and MUC5AC in cultured biliary epithelial cells. This overexpression was inhibited by pretreatment with calphostin C, an inhibitor of protein kinase C. These findings suggest that LPS can induce overexpression of MUC2 and MUC5AC in biliary epithelial cells via synthesis of TNF-alpha and activation of protein kinase C. This mechanism might be involved in the lithogenesis of hepatolithiasis.
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PMID:Lipopolysaccharide induces overexpression of MUC2 and MUC5AC in cultured biliary epithelial cells: possible key phenomenon of hepatolithiasis. 1236 20

Porphyromonas gingivalis is a Gram-negative periodontopathic bacterium colonizing the oral cavity and its lipopolysaccharide (LPS) is a key factor in the development of periodontitis. We investigated the effect of P. gingivalis LPS on the cellular responses associated with mucin synthesis in sublingual salivary gland acinar cells. Exposure of the acinar cells to the LPS led to a dose-dependent decrease in mucin synthesis and was accompanied by a massive induction in inducible nitric oxide synthase (NOS-2) activity and the increase in NO production, caspase-3 activity and apoptosis. Inhibition of extracellular signal-regulated kinase (ERK) with PD98059 accelerated the LPS-induced decrease in the glycoprotein synthesis and caused further increase in apoptosis and NOS-2 activity, while the blockade of p38 mitogen-activated kinase (MAPK) with SB203580 countered the LPS-induced reduction in the glycoprotein synthesis and obviated the induced increases in NOS-2 and apoptosis. Introduction of NOS-2 inhibitor, L-NAME, not only countered the LPS-induced increase in NO generation, caspase-3 activity and apoptosis, but caused the impedance of the LPS inhibition on mucin synthesis. The findings point to the upregulation in NOS-2 expression by P. gingivalis LPS as a key detrimental culprit affecting salivary mucin synthesis.
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PMID:Porphyromonas gingivalis lipopolysaccharide interferes with salivary mucin synthesis through inducible nitric oxide synthase activation by ERK and p38 kinase. 1237 6

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the superfamily of nuclear receptor transcription factors, plays a critical role in the regulation of the expression of genes associated with inflammation. Using mucous acinar cells of sublingual salivary gland, we investigated the effect of PPARgamma activation on the disturbances in salivary mucin synthesis evoked by lipopolysaccharide (LPS) of periodontopathic bacterium, P. gingivalis. Exposure of the acinar cells to the LPS led to a dose-dependent decrease (up to 58.4%) in mucin synthesis, accompanied by a massive enhancement in apoptosis and NO production, and an induction in inducible nitric oxide synthase (NOS-2) activity. Activation of PPARgamma with a specific synthetic agonist, ciglitazone, prevented in a dose-dependent fashion the LPS-induced reduction in mucin synthesis, and the effect was reflected in a marked decrease in apoptosis, NO generation, and the expression of NOS-2 activity. The impedance by ciglitazone of the LPS-induced changes in mucin synthesis was blocked by PD98059, an inhibitor of extracellular signal regulated kinase (ERK), as well as wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K). Moreover, both agents caused further enhancement in the LPS-induced nitric oxide generation and countered the inhibitory effect of ciglitazone on the LPS-induced upregulation in NOS-2. The findings suggest that the impedance of P. gingivalis LPS inhibition of salivary, mucin synthesis by PPARgamma agonist, ciglitazone, involves activation of ERK pathway by PI3K.
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PMID:Activation of peroxisome proliferator-activated receptor gamma impedes Porphyromonas gingivalis lipopolysaccharide interference with salivary mucin synthesis through phosphatidylinositol 3-kinase/erk pathway. 1267 15

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a critical role in the regulation of the expression of genes associated with inflammation. In this study, we report that PPARgamma activation leading to the impedance of H. pylori lipopolysaccharide (LPS) inhibitory effect on gastric mucin synthesis occurs with the involvement of phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways. Using gastric mucosal cells in culture, we show that activation of PPARgamma with a specific synthetic agonist, ciglitazone, prevents in a dose-dependent fashion (up to 90.2%) the LPS-induced reduction in mucin synthesis, and the effect is reflected in a marked decrease in the LPS-induced apoptosis (72.4%), NO generation (80.1%), and the expression of NOS-2 activity (90%). The impedance by ciglitazone of the LPS-induced reduction in mucin synthesis was blocked by wortmannin, a specific inhibitor of P13K and PD98059, an inhibitor of ERK. Both inhibitors, moreover, caused further enhancement in the LPS-induced NO generation and countered the inhibitory effect of ciglitazone on the LPS-induced upregulation in NOS-2. Our findings point to PI3K and ERK as mediators of PPARgamma agonist effect leading to the impedance of H. pylori LPS inhibition on gastric mucin synthesis.
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PMID:Impedance of Helicobacter pylori lipopolysaccharide interference with gastric mucin synthesis by peroxisome proliferator-activated receptor gamma activation involves phosphatidylinositol 3-kinase/ERK pathway. 1274 91

Ectodomain shedding of epidermal growth factor receptor (EGFR) ligands [e.g., transforming growth factor type alpha (TGF-alpha)] and EGFR phosphorylation are implicated in mucin production in airway epithelial cells. Tumor necrosis factor alpha-converting enzyme (TACE) is reported to cleave precursor of TGF-alpha, with release of soluble mature TGF-alpha in various epithelial tissues. We hypothesized that TACE increases the shedding of TGF-alpha, resulting in EGFR phosphorylation and inducing mucin production in human airway epithelial (NCI-H292) cells. To examine this hypothesis, we stimulated NCI-H292 cells with phorbol 12-myristate 13-acetate (PMA, an activator of TACE) and pathophysiologic stimuli [lipopolysaccharide (LPS) and supernatant from the Gram-negative bacterium Pseudomonas aeruginosa (PA sup)]. PMA, PA sup, and LPS increased MUC5AC gene expression and mucin protein production, effects that were prevented by pretreatment with AG1478, a selective inhibitor of EGFR phosphorylation and by preincubation with an EGFR-neutralizing Ab or with a TGF-alpha-neutralizing Ab, implicating ligand (TGF-alpha)-dependent EGFR phosphorylation in mucin production. These stimuli induced release of soluble TGF-alpha, EGFR phosphorylation, and MUC5AC expression, which were blocked by the metalloprotease inhibitors tumor necrosis factor-alpha protease inhibitor-1 and tissue inhibitor of metalloprotease-3. We specifically knocked down the expression of metalloprotease TACE by using small interfering RNA for TACE. Knockdown of TACE inhibited PMA-, PA sup-, and LPS-induced TGF-alpha shedding, EGFR phosphorylation, and mucin production. From these results, we conclude that TACE plays a critical role in mucin production by airway epithelial cells by means of a TACE ligand-EGFR cascade in response to various stimuli.
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PMID:Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. 1297 43

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Here, we identify a cDNA encoding a novel mucin protein, shown previously to be up-regulated in IgAN patients, from a human kidney cDNA library. This protein contains a mucin tandem repeat of 19 amino acids consisting of many threonine, serine, and proline residues and likely to be extensively O-glycosylated; thus, this gene was classified in the mucin family and named MUC20. The human MUC20 gene contains at least four exons and is localized close to MUC4 on chromosome 3q29. We found variations in repeat numbers in the mucin tandem domain, suggesting polymorphism of this region. Northern blot and reverse transcription-PCR analyses revealed that human MUC20 mRNA was expressed most highly in kidney and moderately in placenta, colon, lung, prostate, and liver. Immunohistochemical analysis of human kidney revealed that MUC20 protein was localized in the proximal tubules. Immunoblotting analysis of MUC20 proteins produced in Madin-Darby canine kidney and HEK293 cells indicated the localization of MUC20 protein in a membrane fraction and extensive posttranslational modification. Immunoelectron microscopy of MUC20-producing Madin-Darby canine kidney cells demonstrated that MUC20 protein was localized on the plasma membrane. Expression of MUC20 mRNA in a human kidney cell line was up-regulated by tumor necrosis factor-alpha, phorbol 12-myristate 13-acetate, or lipopolysaccharide. Two species of MUC20 mRNA (hMUC20-L and hMUC20-S), resulting from alternative transcription, were identified in human tissue, whereas only one variant was observed in mouse tissues. Mouse MUC20 mRNA was expressed in the epithelial cells of proximal tubules, and the expression increased dramatically with the progression of lupus nephritis in the kidney of MRL/MpJ-lpr/lpr mice. Moreover, the expression of mouse MUC20 was augmented in renal tissues acutely injured by cisplatin or unilateral ureteral obstruction. These characteristics suggest that the production of MUC20 is correlated with development and progression of IgAN and other renal injuries.
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PMID:Molecular cloning, genomic structure, and expression analysis of MUC20, a novel mucin protein, up-regulated in injured kidney. 1456 53

1. Diosmectite is a natural silicate effectively used in the treatment of infectious diarrhoea. Its antidiarrhoeal properties involve adsorption of toxins and bacteria and modifications of the rheological characteristics of gastrointestinal mucus. Hence, the aim of this study was to test the intestinal anti-inflammatory activity of diosmectite. 2. Diosmectite (500 mg x kg(-1) day(-1), p.o.) was administered as a post-treatment to rats with chronic trinitrobenzene sulphonic acid colitis. Colonic status was checked 1 and 2 weeks after colitis induction by macroscopic, histological and biochemical examination. 3. Diosmectite post-treatment resulted in amelioration of the morphological signs (intestinal weight, macroscopic damage, necrosed area, histology) and biochemical markers (myeloperoxidase activity, glutathione levels, MUC2 expression, inducible nitric oxide synthase and interleukin-1beta (IL-1beta) and leukotriene B(4) synthesis), as well as in the reduction of the severity of diarrhoea. The effect of the clay was comparable to that of sulphasalazine (50 mg x kg(-1) day(-1)). 4. 5. Diosmectite exhibited a dose-dependent capacity to adsorb proteins in vitro as well as a dose-dependent inhibitory effect on the basolateral secretion of IL-8 by lipopolysaccharide (LPS)-stimulated HT29 cells. Diosmectite had a dose-dependent inhibitory effect on IL-1beta production by LPS-stimulated THP-1 cells. 6. The effect of diosmectite on MUC2 was post-transcriptional, since mRNA levels were unaffected. However, diosmectite is able to upregulate MUC2 mRNA levels in HT29-MTX cells. 7. Diosmectite has anti-inflammatory activity administered as a post-treatment. Possible mechanisms include adsorption of luminal antigens, increase of colonic mucin levels and possibly a direct modulatory action of cytokine production by mucosal cells.
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PMID:Anti-inflammatory effect of diosmectite in hapten-induced colitis in the rat. 1499 5

Bacterial infections of the lung are known to induce inflammatory responses, which lead to mucus hypersecretion. Moreover, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and its activation. Furthermore, matrix metalloproteinases (MMPs), especially MMP-9, have been reported to promote the transmigration of activated neutrophils. In this study, we investigated the associations between lipopolysaccharide (LPS)-induced goblet cell (GC) metaplasia and EGFR expression and the effects of MMP inhibitor (MMPI). Various concentrations of LPS were instilled into the tracheas of pathogen-free Sprague-Dawley rats, and airways were examined at different times after LPS instillation. To examine the role of MMP-9, we treated rats 3 days before LPS instillation and daily thereafter with MMPI. Neutrophilic infiltration, Alcian blue/periodic acid-Schiff (AB/PAS) staining, and immunohistochemical staining for MUC5AC, EGFR, and MMP-9 were performed. The instillation of LPS increased AB/PAS and MUC5AC staining in time- and dose-dependent manners, and treatment with MMPI significantly prevented GC metaplasia. The instillation of LPS into the trachea also induced neutrophilic infiltration and EGFR and MMP-9 expression in the airway epithelium, and MMPI was found to significantly prevent neutrophil recruitment, GC metaplasia, and EGFR and MMP-9 expression. This study demonstrates that the MMP-9 and EGFR cascades are associated with LPS-induced mucus hypersecretion.
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PMID:Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia. 1502 Feb 97

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the subfamily of ligand-dependent nuclear transcription factors, plays a key role in the regulation of the expression of genes associated with inflammation. In this study, using gastric mucosal cells in culture, we assess the role of PPARgamma in the disturbances in gastric mucin synthesis and apoptotic processes evoked by Helicobacter pylori lipopolysaccharide (LPS). Exposure of gastric mucosal cells to the LPS led to a concentration-dependent decrease (up to 59.5%) in mucin synthesis, and this effect of the LPS was accompanied by a 6.5-fold increase in apoptosis, induction of COX-2 and NOS-2 protein expression, and the enhancement in PGE(2) generation (18.6-fold) and NOS-2 activity (24.1-fold). However, the expression of COX-1 protein was not affected. Activation of PPARgamma with a specific synthetic agonist, ciglitazone, countered (up to 90.2%) the LPS-induced reduction in mucin synthesis in a concentration-dependent manner, and this effect of the agent was reflected in a marked decrease in COX-2 and NOS-2 protein expression, reduction (up to 72.4%) in apoptosis and a decline (up to 84.1%) in PGE(2) generation and NOS-2 activity (up to 90%). A pronounced prevention (88.2%) in the LPS-induced PGE(2) release and the diminished COX-2 protein expression was also attained with the COX-2-selective inhibitor NS-398, but the effect was not associated with the impedance of the LPS inhibitory effect on mucin synthesis. Our findings thus demonstrate that the detrimental influence of H. pylori LPS on gastric mucin synthesis is closely linked to the increase in proapoptotic processes triggered by NOS-2 upregulation, and that PPARgamma activation obviates this detrimental effect. Hence, pharmacological manipulation of PPARgamma activation may provide therapeutic benefits in countering the disruptive effects of H. pylori on gastric mucosal mucus coat continuity.
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PMID:Peroxisome proliferator-activated receptor gamma activation counters the detrimental effect of Helicobacter pylori lipopolysaccharide on gastric mucin synthesis. 1503 5

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