| AMP-18 facilitates assembly and stabilization of tight junctions to protect the colonic mucosal barrier. | |
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MedLine Citation:
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PMID: 22271547 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Inflammatory bowel disease (IBD) is characterized by an injured epithelium. Development of agents that could enhance mucosal healing is a major goal in IBD therapeutics. The 18-kDa antrum mucosal protein (AMP-18) and a 21-mer peptide derived from AMP-18 stimulate accumulation of tight junction (TJ) proteins in cultured epithelial cells and mouse colonic mucosa to protect the mucosal barrier, suggesting it might be a useful agent to treat IBD. METHODS: We searched for molecular mechanisms by which AMP peptide or recombinant AMP-18 act on TJs in intact cell monolayers, or those disrupted by low-calcium medium. Roles of the p38 mitogen-activated protein kinase (MAPK) / heat shock protein (hsp)25 pathway and PKCζ were investigated by immunoblotting and confocal microscopy. RESULTS: AMP peptide activated p38 MAPK, which subsequently phosphorylated hsp25. Accumulated phospho-hsp25 was associated with perijunctional actin. AMP-18 also induced rapid phosphorylation of PKCζ and its colocalization with perijunctional actin in Caco2/bbe cells, which was accompanied by translocation and formation of complexes of "polarity proteins" in the TJ-containing detergent-insoluble fraction. Treatment with AMP-18 also stimulated accumulation of ZO-1, ZO-2, and JAM-A in nascent TJs known to associate with the multimeric p-PKCζ/Par6/ Cdc42/ECT2·GTP/Par3 polarity protein complex. CONCLUSIONS: AMP-18 facilitates translocation and assembly of multiple proteins into TJs and their association with and subsequent stabilization of the actin filament network. We speculate that improved barrier function induced by AMP-18 is mediated by enhanced TJ assembly. Thus, AMP-18 may provide a promising lead to develop agents effective in healing injured colonic epithelium in IBD. |
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Authors:
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Peili Chen; Sreedharan Kartha; Marc Bissonnette; John Hart; F Gary Toback |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-01-23 |
Journal Detail:
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Title: Inflammatory bowel diseases Volume: 18 ISSN: 1536-4844 ISO Abbreviation: Inflamm. Bowel Dis. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-08-13 Completed Date: 2013-01-17 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9508162 Medline TA: Inflamm Bowel Dis Country: United States |
Other Details:
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Languages: eng Pagination: 1749-59 Citation Subset: IM |
Copyright Information:
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Copyright © 2012 Crohn's & Colitis Foundation of America, Inc. |
Affiliation:
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Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Caco-2 Cells Calcium / metabolism Cells, Cultured Colitis / chemically induced, metabolism, prevention & control* Colon / injuries, metabolism, pathology* Dextran Sulfate / toxicity Fluorescent Antibody Technique, Indirect HSP27 Heat-Shock Proteins / metabolism Humans Intestinal Mucosa / injuries, metabolism, pathology* Male Mice Mice, Inbred C57BL Peptide Fragments / metabolism* Peptide Hormones / metabolism* Phosphorylation Protein Kinase C / metabolism Rats Tight Junctions / physiology* p38 Mitogen-Activated Protein Kinases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA036745/CA/NCI NIH HHS; P30DK42086/DK/NIDDK NIH HHS; R21 DE018811/DE/NIDCR NIH HHS; R21 DE018811-01A2/DE/NIDCR NIH HHS; R21 DE018811-02/DE/NIDCR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/GKN1 protein, human; 0/HSP27 Heat-Shock Proteins; 0/HSPB1 protein, human; 0/Peptide Fragments; 0/Peptide Hormones; 7440-70-2/Calcium; 9042-14-2/Dextran Sulfate; EC 2.7.11.1/protein kinase C zeta; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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