Disaccharides derived from heparin or heparan sulfate regulate IL-8 and IL-1 beta secretion by intestinal epithelial cells.
OBJECTIVE
Intestinal epithelial cells can produce cytokines and chemokines that play an important role in the mucosal immune response. Regulation of this secretion is important to prevent inflammatory tissue damage. Disaccharides derived from heparan sulfate and heparin have been shown to down-regulate inflammation in vivo. We tested the effect of such disaccharides on cytokine secretion by intestinal epithelial cells.


METHODS
Spontaneous and tumor necrosis factor (TNF)-alpha-stimulated interleukin (IL)-8 and IL-1 beta secretion and mRNA expression were assessed in HT-29 and Caco-2 intestinal epithelial cell lines in the presence of a panel of heparin and heparan sulfate disaccharides.


RESULTS
Specific disaccharides suppressed spontaneous and TNF-alpha-induced mediator secretion in a dose-dependent manner. Disaccharide activity was structurally restricted. Preincubation of cells with nonsuppressing disaccharides blocked the activity of suppressing disaccharides. The number of sulfate moieties determined the ability of nonsuppressing disaccharides to block the effect of suppressive disaccharides. No suppression of mRNA expression was noted, and intracellular mediator levels were not reduced.


CONCLUSIONS
Disaccharides derived from heparin and heparan sulfate regulate proinflammatory mediator secretion from intestinal epithelial cells. Dose dependence and competition by structurally diverging disaccharides suggest a receptor-mediated mechanism. Unchanged mRNA and intracellular mediator levels suggest that the disaccharides act at posttranscriptional stages.
Chowers
Y
Y
Department of Gastroenterology, Chaim Sheba Medical Center, Tel-HaShomer, Israel. chowers@netvision.net.il
Lider
O
O
Schor
H
H
Barshack
I
I
Tal
R
R
Ariel
A
A
Bar-Meir
S
S
Cohen
I R
IR
Cahalon
L
L
D000276:Adjuvants, Immunologic / Q000378:metabolism; D000925:Anticoagulants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018938:Caco-2 Cells; D004187:Disaccharides / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004751:Enteritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D019073:HT29 Cells; D006493:Heparin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D000925:Anticoagulants; D004187:Disaccharides; D006493:Heparin; D006497:Heparan Sulfate; D007375:Interleukin-1; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha