A DISACCHARIDE THAT INHIBITS TUMOR-NECROSIS-FACTOR-ALPHA IS FORMED FROM THE EXTRACELLULAR-MATRIX BY THE ENZYME HEPARANASE

The activation of T cells by antigens or mitogens leads to the secreti on of cytokines and enzymes that shape the inflammatory response. Amon g these molecular mediators of inflammation is a heparanase enzyme tha t degrades the heparan sulfate scaffold of the extracellular matrix (E CM). Activated T cells use heparanase to penetrate the ECM and gain ac cess to the tissues. We now report that among the breakdown products o f the ECM generated by heparanase is a trisulfated disaccharide that c an inhibit delayed-type hypersensitivity (DTH) in mice. This inhibitio n of T-cell mediated inflammation in vivo was associated with an inhib itory effect of the disaccharide on the production of biologically act ive tumor necrosis factor alpha (TNF-alpha) by activated T cells in vi tro; the trisulfated disaccharide did not affect T-cell viability or r esponsiveness generally. Both the in vivo and in vitro effects of the disaccharide manifested a bell-shaped dose-response curve. The inhibit ory effects of the trisulfated disaccharide were lost if the sulfate g roups were removed. Thus, the disaccharide, which may be a natural pro duct of inflammation, can regulate the functional nature of the respon se by the T cell to activation. Such a feedback control mechanism coul d enable the T cell to assess the extent of tissue degradation and adj ust its behavior accordingly.