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Loss of cell‐associated heparan sulfate (HS) amplifies IFNγ‐ and TNFα‐induced protein leakage in a model of Protein‐Losing Enteropathy (PLE)
Author(s) -
Bode Lars,
Park Pyong Woo,
Murch Simon,
Freeze Hudson H
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a913-c
Subject(s) - enteropathy , protein losing enteropathy , tumor necrosis factor alpha , heparan sulfate , heparin , immunology , cytokine , proteoglycan , biology , microbiology and biotechnology , chemistry , medicine , biochemistry , extracellular matrix , disease
PLE, the loss of plasma proteins through the intestine, occurs in ostensibly unrelated diseases. Emerging commonalities indicate that genetic insufficiencies predispose for PLE and environmental insults trigger PLE onset which is often associated with viral infections (elevated IFNγ) and a pro‐inflammatory state (elevated TNFα). The specific loss of HS from the basolateral surface of intestinal epithelial cells only during episodes of PLE suggests a possible mechanistic link. We established the first tissue culture model of PLE showing that both HS loss and TNFα alone, but not IFNγ induce protein leakage. However, IFNγ upregulates TNFα‐receptor 1 and enhances TNFα‐mediated protein leakage. HS loss further amplifies the response to IFNγ and TNFα whereas addition of soluble heparin compensates for the loss of cell‐associated HS and alleviates protein leakage. We're currently establishing a mouse model mimicking PLE. Mice genetically deficient in syndecan‐1, the predominant HS proteoglycan on the basolateral surface of intestinal epithelial cells, have increased intestinal protein loss which can be further aggravated by TNFα‐injections. These models may help to guide therapeutic studies using heparin and heparin‐like molecules to treat or even prevent PLE. Supported by Children's Hearts Fund, NIH (R21 HL 078997), and Deutsche Forschungsgemeinschaft (BO 2488/1‐1).