Inhibition of Na+,K+-ATPase by interferon γ down-regulates intestinal epithelial transport and barrier function

Sugi, Kazunori; Musch, Mark W.; Chang, Eugene B.; Field, Michael

doi:10.1053/gast.2001.24045

Cited by 143 publications

(113 citation statements)

References 18 publications

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“…Rather than induction of claudin-2, it appears that TNFa/IFNg may cause a more global tight junction disruption with removal of claudin 4 and other proteins from the tight junction. Many previous studies have been published on the effects of TNFa/ IFNg on gut epithelial cell barriers 29,30,[75][76][77][78][79][80][81] although few studies are published on the response of claudins to inflammatory cytokines. [80][81][82] TNFa/IFNg was reported to promote internalisation of junction adhesion molecule 1, occludin, and claudins 1 and 4 that correlated with large decreases in TER, increases in the passage of 3 kDa FITC-dextran, but no significant changes in protein detection levels on Western blots.…”

Section: Inflammatory Cytokines and Claudin Expressionmentioning

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

430

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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Section: Inflammatory Cytokines and Claudin Expressionmentioning

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

430

384

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“…These effects are mediated at the molecular level by altered expression and/or redistribution of tight junction proteins and perturbations of the actin cytoskeleton (Youakim and Ahdieh, 1999;Bruewer et al, 2003). Recent evidence suggests that IFN␥-mediated inhibition of epithelial Na + ,K + -ATPase activity plays a critical role in initiating the signalling pathways that lead to barrier disruption (Sugi et al, 2001;Bertelsen et al, 2004). Despite these studies, our understanding of how IFN␥ modulates the paracellular pore at the functional level, and how this might affect intestinal permeability to antigens, remains limited.…”

Section: Introductionmentioning

confidence: 99%

Interferon-γ selectively increases epithelial permeability to large molecules by activating different populations of paracellular pores

Watson

Hoare

Garrod

et al. 2005

Journal of Cell Science

153

109

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Impairment of the gut epithelial barrier by agents such as IFNγ may play a key role in the pathogenesis of inflammatory disorders by increasing the paracellular penetration of luminal macromolecules, potentially including bacterial antigens. Owing to limitations of current paracellular probes, little is known about the precise functional changes induced by IFNγ and how these relate to the development of increased macromolecular permeability. Here we investigate how IFNγ modulates this pathway in T84 monolayers using a novel profiling technique that resolves different populations of paracellular pores by simultaneous analysis of 24 permeability probes of defined molecular size. Two types of functional pore present in control monolayers, an abundant restrictive pore with a radius of ∼4.5 Å and a much larger but infrequent, non-restrictive pore, were differentially regulated by IFNγ. Incubation with IFNγ dose-dependently and reversibly increased the frequency of the non-restrictive pores while having no significant effect on the restrictive component. Cytokine-induced increases in β, the descriptor of the non-restrictive pore, correlated closely with increased permeability to large molecules (10 kDa) including E. coli-derived lipopolysaccharide, but not small (0.182 kDa) molecules. This effect was associated with changes in expression of the tight junction proteins occludin and claudin-1. These data suggest that IFNγ selectively increases the transepithelial flux of large molecules by activating specific pathways within the junctional pore. One hypothesis is that this process may be activated in the early stages of the inflammatory response, facilitating the passage of large and potentially antigenic molecules across the gut without gross disruption of the barrier to small molecules.

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“…Numerous studies have examined IFN-␥-and TNF-␣-induced changes in epithelial paracellular permeability. Variable effects of these cytokines on the TJ cytoplasmic plaque protein ZO-1 and TJ structure have been reported (15)(16)(17)(18)(19)(20)(21)(22). Given these diverse reports and to understand the mechanisms by which proinflammatory cytokines such as IFN-␥ and TNF-␣ enhance paracellular permeability, we analyzed in detail the influence of these cytokines on the AJC.…”

mentioning

confidence: 99%

Proinflammatory Cytokines Disrupt Epithelial Barrier Function by Apoptosis-Independent Mechanisms

Bruewer

Luegering

Kucharzik

et al. 2003

The Journal of Immunology

793

643

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It is well known that inflammatory conditions of the intestinal mucosa result in compromised barrier function. Inflammation is characterized by an influx into the mucosa of immune cells that influence epithelial function by releasing proinflammatory cytokines such as IFN-γ and TNF-α. Mucosal barrier function is regulated by the epithelial apical junctional complex (AJC) consisting of the tight junction and the adherens junction. Since the AJC regulates barrier function, we analyzed the influence of IFN-γ and TNF-α on its structure/function and determined the contribution of apoptosis to this process using a model intestinal epithelial cell line, T84, and IFN-γ and TNF-α. AJC structure/function was analyzed by confocal microscopy, biochemical analysis, and physiologic measurement of epithelial gate/fence function. Apoptosis was monitored by determining cytokeratin 18 cleavage and caspase-3 activation. IFN-γ induced time-dependent disruptions in epithelial gate function that were potentiated by coincubation with TNF-α. Tight junction fence function was somewhat disrupted. Cytokine treatment was associated with internalization of AJC transmembrane proteins, junction adhesion molecule 1, occludin, and claudin-1/4 with minimal effects on the cytoplasmic plaque protein zonula occludens 1. Detergent solubility profiles of junction adhesion molecule 1 and E-cadherin and their affiliation with “raft-like” membrane microdomains were modified by these cytokines. Inhibition of cytokine-induced apoptosis did not block induced permeability defects; further emphasizing their primary influence on the epithelial AJC structure and barrier function. Our findings for the first time clearly separate the proapoptotic effects of IFN-γ and TNF-α from their abilities to disrupt barrier function.

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Inhibition of Na+,K+-ATPase by interferon γ down-regulates intestinal epithelial transport and barrier function

Cited by 143 publications

References 18 publications

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

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

Interferon-γ selectively increases epithelial permeability to large molecules by activating different populations of paracellular pores

Proinflammatory Cytokines Disrupt Epithelial Barrier Function by Apoptosis-Independent Mechanisms

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