title: A disaccharide that inhibits tumor necrosis factor alpha is formed from the extracellular matrix by the enzyme heparanase.
abstract: The activation of T cells by antigens or mitogens leads to the secretion of cytokines and enzymes that shape the inflammatory response. Among these molecular mediators of inflammation is a heparanase enzyme that degrades the heparan sulfate scaffold of the extracellular matrix (ECM). Activated T cells use heparanase to penetrate the ECM and gain access to the tissues. We now report that among the breakdown products of the ECM generated by heparanase is a trisulfated disaccharide that can inhibit delayed-type hypersensitivity (DTH) in mice. This inhibition of T-cell mediated inflammation in vivo was associated with an inhibitory effect of the disaccharide on the production of biologically active tumor necrosis factor alpha (TNF-alpha) by activated T cells in vitro; the trisulfated disaccharide did not affect T-cell viability or responsiveness generally. Both the in vivo and in vitro effects of the disaccharide manifested a bell-shaped dose-response curve. The inhibitory effects of the trisulfated disaccharide were lost if the sulfate groups were removed. Thus, the disaccharide, which may be a natural product of inflammation, can regulate the functional nature of the response by the T cell to activation. Such a feedback control mechanism could enable the T cell to assess the extent of tissue degradation and adjust its behavior accordingly.
authors.affiliation: Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Lider
authors.forename: L
authors.initials: L
authors.lastname: Cahalon
authors.forename: D
authors.initials: D
authors.lastname: Gilat
authors.forename: R
authors.initials: R
authors.lastname: Hershkoviz
authors.forename: D
authors.initials: D
authors.lastname: Siegel
authors.forename: R
authors.initials: R
authors.lastname: Margalit
authors.forename: O
authors.initials: O
authors.lastname: Shoseyov
authors.forename: I R
authors.initials: IR
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002240:Carbohydrate Sequence; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002850:Chromatography, Gel; D003315:Cornea / Q000737:chemistry; D004187:Disaccharides / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D004727:Endothelium / Q000737:chemistry; D005109:Extracellular Matrix / Q000378:metabolism*; D005246:Feedback; D005260:Female; D005966:Glucuronidase; D006026:Glycoside Hydrolases / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D006968:Hypersensitivity, Delayed / Q000517:prevention & control*; D007249:Inflammation; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D008969:Molecular Sequence Data; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000099175:Heparanase
chemical_list: D004187:Disaccharides; D005966:Glucuronidase; D006026:Glycoside Hydrolases; D006493:Heparin; D014409:Tumor Necrosis Factor-alpha; D000099175:Heparanase