Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium.

Molmenti, Ernesto P.; Perlmutter, David H.; Rubin, Deborah C.

doi:10.1172/jci116797

Cited by 122 publications

(84 citation statements)

References 35 publications

(36 reference statements)

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“…Trypsin, also present as an inactive zymogen in Paneth cells, is believed to be the serine protease that converts proHD5 to the mature active form in the intestine (2,45). Although Caco2 cells produce trypsin, they also express ␣1-antitrypsin (47,48). Our finding of only proHD5, and not mature peptide, in the culture medium of cells treated with FGF9 is not surprising in view of their production of ␣1-antitrypsin and given the additional presence of serum ␣1-antitrypsin in the growth medium.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways

Brodrick

Vidrich

Porter

et al. 2011

Journal of Biological Chemistry

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Fibroblast growth factor receptor-3 (FGFR-3Despite the critical importance of Paneth cells in maintaining gut homeostasis, knowledge of the pathways regulating Paneth cell differentiation and function has only recently begun to emerge. Studies using transgenic mice or mice with targeted mutations in epithelial regulatory genes, including components of the Wnt signaling pathway (Tcf4, Fz5, Sox9, and Apc), FGFR-3, and PPAR␤/␦, have identified these genes as key regulators of Paneth cell differentiation and expression of defensin peptides in vivo (9 -14). However, the lack of an adequate intestinal epithelial cell culture system that can recapitulate features of Paneth cell differentiation and maturation has hampered direct investigation of how these signaling pathways may interact in regulating Paneth cell differentiation and functional maturation.We recently reported that signaling through FGFR-3 in crypt epithelial cells regulates both the number of epithelial stem cells and Paneth cell differentiation during postnatal gut development (13,15). FGFR-3 is highly expressed along the membranes of cells in the lower portion of the crypt in the developing mouse intestine (15). FGFRs are members of the receptor-tyrosine kinase family. Ligand binding induces dimerization, autophosphorylation, and initiation of a signal transduction cascade that ultimately results in modification of gene expression. Ligands for FGFR-3, FGF1, FGF2, and FGF9, are up-regulated in the postnatal murine small intestine from birth through the suckling weaning transition, when crypt mor-

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Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways

Brodrick

Vidrich

Porter

et al. 2011

Journal of Biological Chemistry

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“…a1-PI is primarily a liver-derived serum protein with a molecular weight between 52 and 55 kDa. Recent studies showed that a1-PI is also synthesized outside the liver: by alveolar epithelial cells [3], monocytes [4], chondrocytes [5], human cornea [6] and, of importance for local control of inflammatory processes in the gut, in intestinal epithelial cells [7].…”

Section: Introductionmentioning

confidence: 99%

Regulation ofα1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells

Faust

Raschke

Hormann

et al. 2002

Clinical and Experimental Immunology

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SUMMARYa1-Proteinase inhibitor (a1-PI) is the main serine proteinase inhibitor in human plasma. Apart from its synthesis in the liver, this anti-inflammatory protein is also synthesized by and excreted from human intestinal epithelial cells. Antiinflammatory actions of a1-PI are thought to be of relevance in the pathogenesis of inflammatory bowel disease. To investigate the role of macrophage-derived cytokines on a1-PI secretion from intestinal epithelial cells, we cultured Caco-2 cells until differentiation (14 days in culture) on permeable filter supports. Monolayers of differentiated Caco-2 cells were then co-cultured with human peritoneal macrophages, grown on plastic in the basolateral chamber. Under these conditions, a1-PI secretion from Caco-2 cells was enhanced by 45%, probably by a direct action of macrophage-derived cytokines on Caco-2 cells. To extend this observation further, we treated differentiated Caco-2 cells with macrophage-derived proinflammatory cytokines (IL-1b, IL-8, TNF-a), as well as with lymphocyte-derived cytokines IL-2, IL-6 and IFN-g. As early as after 24 h treatment, IL-2 and IL-8 induced a significant and dose-dependent increase of a-1-PI secretion into cell culture medium; this effect was completely reversed after immunoneutralization by the antibodies against IL-2 and IL-8 a1-PI secretion was only slightly decreased after treatment with IFN-g, while IL-1b, IL-6 and TNFa had no effect. a1-PI secretion correlated well with the expression of this protein in differentiated Caco-2 cells after cytokine treatment, as confirmed by Western blot. Our data imply that, in vitro, a1-PI secretion in enterocyte-like Caco-2 cells is up-regulated by IL-2 and IL-8. Our results suggest that both lymphocyte-and macrophage-derived cytokines regulate secretion of the anti-inflammatory protein a1-PI in intestinal epithelial cells.

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“…It is produced predominantly by hepatocytes but also by blood monocytes, macrophages, pulmonary alveolar cells, and intestinal epithelial cells (20,21). The biological activity of AAT can be affected by point mutations modifying its structure and/or secretion.…”

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confidence: 99%

Detection of Circulating and Endothelial Cell Polymers of Z and Wild Type α1-Antitrypsin by a Monoclonal Antibody

Janciauskiene¹,

Dominaitiene²,

Sternby³

et al. 2002

Journal of Biological Chemistry

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Globular inclusions of abnormal ␣1-antitrypsin (AAT)in the endoplasmic reticulum of hepatocytes are a characteristic feature of AAT deficiency of the PiZZ phenotype. Monoclonal antibodies, which contain constant specificity and affinity, are often used for the identification of Z-mutation carriers. A mouse monoclonal antibody (ATZ11) raised against PiZZ hepatocytic AAT was successfully used in enzyme-linked immunosorbent assays (ELISA) and in identification of Z-related AAT globular inclusions by immunohistochemical techniques. Using electrophoresis, Western blotting, and ELISA procedures, we have shown in the present study that this monoclonal antibody specifically detects a conformationdependent neoepitope on both polymerized and elastase-complexed molecular forms of AAT. The antibody has no apparent affinity for native, latent, or cleaved forms of AAT. The antibody ATZ11 illustrates the structural resemblance between the polymerized form of AAT and its complex with elastase and provides evidence that Z-homozygotes beyond the native form may have at least one more circulating molecular form of AAT, i.e. its polymerized form. In addition, staining of endothelial cells with ATZ11 antibody in both M-and Z-AAT individuals shows that AAT attached to endothelial cells is in a polymerized form. The antibody can be a powerful tool for the study of the molecular profile of AAT, not only in Z-deficiency cases but also in other (patho)physiological conditions.The capacity to undergo conformational changes is crucial for the physiological function of many proteins; the serine proteinase inhibitors (serpins) 1 are a clear case for such changes having been exploited during evolution as a means of modulating inhibitory activity (1). Serpins possess two structural elements that are conformationally labile and are essential for efficient proteinase inhibition: a reactive center loop and a ␤-sheet (␤-sheet A) that is able to open and accommodate the reactive center loop after its cleavage by the attacking proteases (2-5). The x-ray crystal structures of native, cleaved, cleaved in complex with protease, and polymerized forms of serpins have confirmed the abilities of these proteins to undergo profound conformational changes under certain environmental conditions (6 -8). The crystal structure of the ␣1-antitrypsin-trypsin complex showed complete insertion of the reactive site loop, which substantially increases thermal and conformational stability of the serpin and results in the irreversible inhibition and then the structural destruction of the proteinase (9).The conformational changes that occur in the serpin molecule during the formation of the enzyme-serpin complexes, interaction with other molecules, polymerization, cleavage, and oxidation lead to the generation of conformation-dependent neoepitopes (10). Immunochemical analysis by means of monoclonal antibodies is a useful approach for study of the formation of new epitopes that occur as a result of the conformational polymorphism of serpins (11,12). For example, the sugge...

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Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium.

Cited by 122 publications

References 35 publications

Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways

Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways

Regulation ofα1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells

Detection of Circulating and Endothelial Cell Polymers of Z and Wild Type α1-Antitrypsin by a Monoclonal Antibody

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