Epithelial permeability to proteins in the noninflamed ileum of Crohn's disease?

Söderholm, Johan D.; Peterson, Kajsa Holmgren; Olaison, Gunnar; Franzén, Lennart; Weström, Björn; Magnusson, Karl‐Eric; Sjödahl, Rune

doi:10.1016/s0016-5085(99)70551-2

Cited by 182 publications

(133 citation statements)

References 36 publications

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“…The ability of PKC-to affect the architectural organization and permeability of intestinal cells in monolayers could lead to development of new therapeutic modalities for a variety of intestinal disorders, especially IBD, where loss of mucosal permeability function has been found (Hollander, 1992(Hollander, , 1998Keshavarzian et al, 1992Keshavarzian et al, , 1999Peeters et al, 1994;Hermiston andGordon, 1995, 2003;Soderholm et al, 1999). The pathophysiology of IBD, which includes ulcerative colitis and Crohn's disease, oscillates between active (symptomatic) phases of disorder when mucosal permeability is increased, and inactive (asymptomatic) phases when mucosal permeability is low.…”

Section: Discussionmentioning

confidence: 99%

“…Loss of barrier function (i.e., increased permeability) is thought to lead to the penetration of bacterial derivatives and other harmful immunoreactive antigens into the mucosa and to cause the initiation or perpetuation of inflammatory processes and tissue injury (Hollander, 1992(Hollander, , 1998Hermiston and Gordon, 1995;Keshavarzian et al, 1999;Banan et al, 2000a). Indeed, disruption of barrier function ("leaky gut") has been implicated in the pathogenesis of several gastrointestinal and systemic disorders, including inflammatory bowel disease (IBD) (Hollander, 1992(Hollander, , 1998Keshavarzian et al, 1992Keshavarzian et al, , 1999Keshavarzian et al, , 2003Peeters et al, 1994;Hermiston and Gordon, 1995;Soderholm et al, 1999). Not surprisingly, one of the key difficulties in managing IBD patients stems from our incomplete understanding of the processes regulating intestinal barrier function.…”

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confidence: 99%

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θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

Banan¹,

Zhang²,

Shaikh³

et al. 2005

J Pharmacol Exp Ther

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Using monolayers of intestinal Caco-2 cells, we discovered that the isoform of protein kinase C (PKC), a member of the "novel" subfamily of PKC isoforms, is required for monolayer barrier function. However, the mechanisms underlying this novel effect remain largely unknown. Here, we sought to determine whether the mechanism by which PKC-disrupts monolayer permeability and dynamics in intestinal epithelium involves PKC--induced alterations in claudin isotypes. We used cell clones that we recently developed, clones that were transfected with varying levels of plasmid to either stably suppress endogenous PKC-activity (antisense, dominant-negative constructs) or to ectopically express PKC-activity (sense constructs). We then determined barrier function, claudin isotype integrity, PKC-subcellular activity, claudin isotype subcellular pools, and claudin phosphorylation. Antisense transfection to underexpress the PKC-led to monolayer instability as shown by reduced 1) endogenous PKC-activity, 2) claudin isotypes in the membrane and cytoskeletal pools (2claud-1, 2claud-4 assembly), 3) claudin isotype phosphorylation (2 phospho-serine, 2 phospho-threonine), 4) architectural stability of the claudin-1 and claudin-4 rings, and 5) monolayer barrier function. In these antisense clones, PKC-activity was also substantially reduced in the membrane and cytoskeletal cell fractions. In wild-type (WT) cells, PKC-(82 kDa) was both constitutively active and coassociated with claudin-1 (22 kDa) and claudin-4 (25 kDa), forming endogenous PKC-/claudin complexes. In a second series of studies, dominant-negative inhibition of the endogenous PKC-caused similar destabilizing effects on monolayer barrier dynamics, including claudin-1 and -4 hypophosphorylation, disassembly, and architectural instability as well as monolayer disruption. In a third series of studies, sense overexpression of the PKC-caused not only a mostly cytosolic distribution of this isoform (i.e., Ͻ12% in the membrane ϩ cytoskeletal fractions, indicating PKC-inactivity) but also led to disruption of claudin assembly and barrier function of the monolayer. The conclusions of this study are that PKC-activity is required for normal claudin assembly and the integrity of the intestinal epithelial barrier. These effects of PKC-are mediated at the molecular level by changes in phosphorylation, membrane assembly, and/or organization of the subunit components of two barrier function proteins: claudin-1 and claudin-4 isotypes. The ability of PKC-to alter the dynamics of permeability protein claudins is a new function not previously ascribed to the novel subfamily of PKC isoforms.The epithelium of the intestinal mucosa is the largest interface between the body and the external environment. An important characteristic of this interface is its ability to maintain a highly selective permeability barrier that protects the internal milieu from hostile factors in the lumenal environment. Barrier permeability, which in general is maintained by epithelial tight-junctional proteins, pe...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

Banan¹,

Zhang²,

Shaikh³

et al. 2005

J Pharmacol Exp Ther

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“…A number of clinical studies have demonstrated an increased intestinal permeability in IBD, especially in Crohn's disease patients and first-degree relatives, where it has been suggested that a primary disorder of intestinal permeability constitutes an etiological factor in the pathogenesis (Ma, 1997;Soderholm et al, 1999). Transgenic IBD models that retain a complete repertoire of immune effectors have clearly demonstrated the relative importance that loss of epithelial integrity plays in driving subsequent abnormal mucosal inflammation and neoplasia.…”

Section: Pathophysiology Of Enteric Glial Cells In Relation To Inflammentioning

confidence: 99%

Role of enteric glial cells in inflammatory bowel disease

Cabarrocas

Savidge

Liblau

2002

Glia

159

154

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Enteric glial cells (EGCs) represent an extensive but relatively poorly described cell population within the gastrointestinal tract. Accumulating data suggest that EGCs represent the morphological and functional equivalent of CNS astrocytes within the enteric nervous system (ENS). The EGC network has trophic and protective functions toward enteric neurons and is fully implicated in the integration and the modulation of neuronal activities. Moreover, EGCs seem to be active elements of the ENS during intestinal inflammatory and immune responses, sharing with astrocytes the ability to act as antigen-presenting cells and interacting with the mucosal immune system via the expression of cytokines and cytokine receptors. Transgenic mouse systems have demonstrated that specific ablation of EGC by chemical ablation or autoimmune T-cell targeting induces an intestinal pathology that shows similarities to the early intestinal immunopathology of Crohn's disease. EGCs may also share with astrocytes the ability to regulate tissue integrity, thereby postulating that similar interactions to those observed for the blood-brain barrier may also be partly responsible for regulating mucosal and vascular permeability in the gastrointestinal tract. Disruption of the EGC network in Crohn's disease patients may represent one possible cause for the enhanced mucosal permeability state and vascular dysfunction that are thought to favor mucosal inflammation. GLIA 41:81-93, 2003.

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“…The passage of antigens across this barrier must be regulated since inappropriate immune responses to the normal flora are believed to contribute to the development of inflammatory bowel disease (IBD). 1 For example, between 10 and 20% presymptomatic Crohn's disease (CD) patients have been shown to have increased gut permeability, 2,3 the noninflamed ileum of Crohn's patients exhibited increased permeability to proteins 4 and increased intestinal epithelial permeability has been shown to precede clinical relapse in some asymptomatic CD patients. [5][6][7] Mutations in the human DLG 5 gene, encoding a protein involved in epithelial barrier differentiation, are a risk factor for CD.…”

mentioning

confidence: 99%

Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells

Prasad

Mingrino

Kaukinen

et al. 2005

Laboratory Investigation

426

384

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Claudin proteins comprise a recently described family of tight junction proteins that differentially regulate paracellular permeability. Since other tight junction proteins show alterations in distribution or expression in inflammatory bowel disease (IBD) we assessed expression of claudins (CL) 2, 3 and 4 in IBD. CL 2 was strongly expressed along the inflamed crypt epithelium, whilst absent or barely detectable in normal colon. In contrast, CL 3 and 4 were present throughout normal colonic epithelium and were reduced or redistributed in the diseased surface epithelium. In a T84-cell culture model of the gut barrier, paracellular permeability decreased with time after plating and correlated with a marked decrease in the expression of CL 2. Addition of IFNc/TNFa led to further decreases in CL 2 and 3, the redistrbution of CL 4 and a marked increase in paracellular permeability. Conversely, IL-13 dramatically increased CL 2, with little effect on CL 3 or 4, but also resulted in increased paracellular permeability. Expression of CL 2 did not correlate with proliferation or junctional reorganisation after calcium ion depletion. Re-expression of CL 2 in response to IL-13 was inhibited by phophatidylinositol 3 kinase inhibitor, LY294002, which also restored the ion permeability to previous levels. CL 2 expression could be stimulated in the absence of IL-13 by activation of phospho-Akt in the phophatidylinositol 3 kinase pathway. These results suggest that INFc/TNFa and IL-13 have differential effects on CL 2, 3 and 4 in tight junctions, which may lead to increased permeability via different mechanisms.

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Epithelial permeability to proteins in the noninflamed ileum of Crohn's disease?

Cited by 182 publications

References 36 publications

θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

Role of enteric glial cells in inflammatory bowel disease

Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells

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