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J. Biol. Chem., Vol. 281, Issue 12, 7809-7815, March 24, 2006

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

Lars Bode, Simon Murch, and Hudson H. Freeze¹

From the Burnham Institute for Medical Research, Glycobiology and Carbohydrate Chemistry Program, La Jolla, California 92037 and Warwick Medical School, Clinical Sciences Research Institute, Coventry CV2 2DX, United Kingdom

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 post-Fontan 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.

Received for publication, September 30, 2005 , and in revised form, December 19, 2005.

^* This work was supported by National Institutes of Health Grant R21 HL 078997, by the Children's Hearts Fund, Buffalo, NY, and by Deutsche Forschungsgemeinschaft Research Fellowship BO 2488/1-1 (to L. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work is dedicated to the memory of Violet Niles, Colin Colson, and Jason Mikula.

¹ To whom correspondence should be addressed: Glycobiology and Carbohydrate Chemistry Program, Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3142; Fax: 858-713-6281; E-mail: hudson{at}burnham.org.

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