Enhanced Production of Interferon-gamma as a Possible Cause of Protein-losing Enteropathy After Modified Fontan Operation

Shimizu, Toshiaki; Nagata, Satoru; Fujii, Tohru; Takahashi, Ken; Kishiro, Masahiko; Ohkubo, Mataichi; Akimoto, Katsumi; Yamashiro, Yuichiro

doi:10.1097/00005176-200310000-00019

Cited by 24 publications

(25 citation statements)

References 9 publications

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“…often associated with increased IFN-γ levels (13). We previously showed in HT29 cells that 12 hours of exposure to IFN-γ upregulates TNFR1 expression and amplifies TNF-α-induced protein leakage (11).…”

Section: Ifn-γ Upregulates Tnfr1 and Amplifies Tnf-α-induced Leakagementioning

confidence: 99%

See 1 more Smart Citation

Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function

Bode

Salvestrini²,

Park³

et al. 2008

J. Clin. Invest.

132

125

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Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-γ, TNF-α, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate-or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-γ, TNF-α, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.

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Section: Ifn-γ Upregulates Tnfr1 and Amplifies Tnf-α-induced Leakagementioning

confidence: 99%

“…It is episodic, and the onset is often associated with viral infections and increased IFN-γ levels (12,13) as well as with a proinflammatory state and increased TNF-α levels (14). IFN-γ and TNF-α disrupt tight junctions (15)(16)(17) and induce paracellular protein leakage (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function

Bode

Salvestrini²,

Park³

et al. 2008

J. Clin. Invest.

132

125

View full text Add to dashboard Cite

show abstract

“…The evidence for this is that patients do not suffer from PLE continuously; rather, PLE is episodic. Its onset is often associated with viral infections and a pro-inflammatory state (2,(5)(6)(7)(8), indicating that multiple factors combine to trigger PLE. Most intriguing is the loss of heparan sulfate (HS) proteoglycans (HSPG) specifically from the basolateral surface of intestinal epithelial cells only during PLE episodes (1, 2, 9, 10) followed by its reappearance when PLE resolves (2).…”

mentioning

confidence: 99%

“…Consistent with this hypothesis, seven out of eight post-Fontan patients have been diagnosed with viral infections at the onset of PLE symptoms (5), indicating that this additional insult triggered PLE. Jejunal biopsies, taken during episodes with PLE, revealed an increased IFN␥ concentration (7), most likely as a response to the viral infection and elevated levels of the pro-inflammatory cytokine TNF␣ (6). Both cytokines are known to impair the integrity of the intestinal epithelial barrier (13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Heparan Sulfate Plays a Central Role in a Dynamic in Vitro Model of Protein-losing Enteropathy

Bode

Murch

Freeze

2006

Journal of Biological Chemistry

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Protein-losing enteropathy (PLE), the loss of plasma proteins through the intestine, is a symptom in ostensibly unrelated diseases. Emerging commonalities indicate that genetic insufficiencies predispose for PLE and environmental insults, e.g. viral infections and inflammation, trigger PLE onset. The specific loss of heparan sulfate (HS) from the basolateral surface of intestinal epithelial cells only during episodes of PLE suggests a possible mechanistic link. In the first tissue culture model of PLE using a monolayer of intestinal epithelial HT29 cells, we proved that HS loss directly causes protein leakage and amplifies the effects of the proinflammatory cytokine tumor necrosis factor ␣ (TNF␣). Here, we extend our in vitro model to assess the individual and combined effects of HS loss, interferon ␥ (IFN␥), TNF␣, and increased pressure, and find that HS plays a central role in the patho-mechanisms underlying PLE. Increased pressure, mimicking venous hypertension seen in postFontan PLE patients, substantially increased protein leakage, but HS loss, IFN␥, or TNF␣ alone had only minor effects. However, IFN␥ up-regulated TNFR1 expression and amplified TNF␣-induced protein leakage. IFN␥ and TNF␣ compromised the integrity of the HT29 monolayer and made it more susceptible to increased pressure. HS loss itself compromises the integrity of the monolayer, amplifying the effects of pressure, but also amplifies the effects of both cytokines. In the absence of HS a combination of increased pressure, IFN␥, and TNF␣ caused maximum protein leakage. Soluble heparin fully compensated for HS loss, providing a reasonable explanation for patient favorable response to heparin therapy.

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“…Patients with low lymphocyte count, especially CD4+ and CD5, seem prone to PLE 65 . Shimilu et al 66 have recently shown that increased interferon gamma in the intestinal mucosa leads to protein loss not accompanied by epithelial changes under electronic microscopy. Agreeing with Chakrabarti, in 2003 20 , the information above indicates that determining the immunological profile of the operated patient seems to be important.…”

Section: Preventionmentioning

confidence: 99%

Enteropatia perdedora de proteínas após cirurgia de Fontan

Amaral

Atik

2006

Arq. Bras. Cardiol.

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Enhanced Production of Interferon-gamma as a Possible Cause of Protein-losing Enteropathy After Modified Fontan Operation

Cited by 24 publications

References 9 publications

Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function

Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function

Heparan Sulfate Plays a Central Role in a Dynamic in Vitro Model of Protein-losing Enteropathy

Enteropatia perdedora de proteínas após cirurgia de Fontan

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