Interleukin-2 Receptor β Subunit-dependent and -independent Regulation of Intestinal Epithelial Tight Junctions

Nishiyama, Raisuke; Sakaguchi, Takanori; Kinugasa, Tetsushi; Gu, Xiubin; MacDermott, Richard P.; Podolsky, Daniel K.; Reinecker, Hans Christian

doi:10.1074/jbc.m106013200

Cited by 59 publications

(42 citation statements)

References 69 publications

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“…Under control conditions, the transmembrane tight junction protein, occludin was expressed as a 65 kDa band in both soluble and insoluble fractions. However the insoluble pool also contained a heterogeneous mixture of polypeptides of higher molecular mass indicative of hyper-phosphorylated forms of the protein (Nishiyama et al, 2001). IFN␥ treatment for 48 hours resulted in a dramatic decrease in the levels of occludin bands of higher molecular mass in the insoluble fraction.…”

Section: Journal Of Cellmentioning

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

151

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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Section: Journal Of Cellmentioning

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

151

109

View full text Add to dashboard Cite

show abstract

“…Multiple second messenger pathways have been found to modulate permeability characteristics of developing and mature junctions by modification of various junctional proteins' phosphorylation state and/or linkage to the actin cytoskeleton (9,(12)(13)(14)(15). Furthermore, actin-myosin interactions, promoted by phosphorylation of the 20-kDa regulatory myosin L chain (MLC), control the contractility of actomyosin in nonmuscle cells (16).…”

mentioning

confidence: 99%

“…The TJ undergoes dynamic physiological changes when stimulated by various mediators, such as cytokines (8,9) and microbial toxins (10,11). Multiple second messenger pathways have been found to modulate permeability characteristics of developing and mature junctions by modification of various junctional proteins' phosphorylation state and/or linkage to the actin cytoskeleton (9,(12)(13)(14)(15).…”

mentioning

confidence: 99%

Neutrophil Transepithelial Migration: Evidence for Sequential, Contact-Dependent Signaling Events and Enhanced Paracellular Permeability Independent of Transjunctional Migration

Edens

Levi

Jaye

et al. 2002

The Journal of Immunology

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Active migration of polymorphonuclear leukocytes (PMN) through the intestinal crypt epithelium is a hallmark of inflammatory bowel disease and correlates with patient symptoms. Previous in vitro studies have shown that PMN transepithelial migration results in increased epithelial permeability. In this study, we modeled PMN transepithelial migration across T84 monolayers and demonstrated that enhanced paracellular permeability to small solutes occurred in the absence of transepithelial migration but required both PMN contact with the epithelial cell basolateral membrane and a transepithelial chemotactic gradient. Early events that occurred before PMN entering the paracellular space included increased permeability to small solutes (<500 Da), enhanced phosphorylation of regulatory myosin L chain, and other as yet undefined proteins at the level of the tight junction. No redistribution or loss of tight junction proteins was detected in these monolayers. Late events, occurring during actual PMN transepithelial migration, included redistribution of epithelial serine-phosphorylated proteins from the cytoplasm to the nucleus in cells adjacent to migrating PMN. Changes in phosphorylation of multiple proteins were observed in whole cell lysates prepared from PMN-stimulated epithelial cells. We propose that regulation of PMN transepithelial migration is mediated, in part, by sequential signaling events between migrating PMN and the epithelium.

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“…Therefore, IL-15 has protective effects for IEC. Besides the novel role of IL-15 on IEC apoptosis described in this manuscript, a previously described IL-15-induced enhanced production of tight-junction proteins and the ensuing increase in transepithelial resistance [48] may contribute to epithelial protection, and further explain the increased epithelial damage following neutralization of IL-15 in DSS-induced colitis.…”

Section: Discussionmentioning

confidence: 52%

IL‐15 protects intestinal epithelial cells

et al. 2006

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IL‐15, a T‐cell growth factor, has been shown to be increased in inflammatory bowel disease (IBD). It has been suggested that neutralization of IL‐15 could protect from T cell‐dependent autoimmune inflammation. On the other hand, an anti‐apoptotic effect of IL‐15 has been demonstrated in kidney epithelial cells during nephritis. We therefore tested the role of IL‐15 in two different experimental models of colitis in vivo, and in models of intestinal epithelial cell (IEC) apoptosis in vitro. IL‐15 blockade in chronic dextran sulphate sodium‐induced colitis resulted in aggravation of the disease with a significantly 2.1‐fold increased epithelial damage score compared to controls. TUNEL staining clearly revealed increased apoptosis. IL‐6, TNF and IFN‐γ secretion by mesenteric lymph node cells were increased. In the T cell‐dependent SCID transfer model of colitis IL‐15 neutralization reduced the inflammatory infiltration and proinflammatory cytokine production. Despite that, the intestinal epithelial damage was not reduced. In vitro, IL‐15 pre‐incubation prevented up to 75% of CH11 antibody‐induced apoptosis in SW‐480 cells and reduced caspase‐3 activity. According to this, endogenously produced IL‐15 in chronic colitis does not only act as a proinflammatory cytokine but has at the same time the potential to reduce mucosal damage by preventing IEC apoptosis.

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Interleukin-2 Receptor β Subunit-dependent and -independent Regulation of Intestinal Epithelial Tight Junctions

Abstract: Interleukin (IL)-

Cited by 59 publications

References 69 publications

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

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

Neutrophil Transepithelial Migration: Evidence for Sequential, Contact-Dependent Signaling Events and Enhanced Paracellular Permeability Independent of Transjunctional Migration

IL‐15 protects intestinal epithelial cells

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