HEPARIN DISACCHARIDES INHIBIT TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION BY MACROPHAGES AND ARREST IMMUNE INFLAMMATION IN RODENTS

Inflammation is the clinical expression of chemical mediators such as the pro-inflammatory cytokine tumor necrosis factor (TNF-)-alpha produ ced by macrophages and other cells activated in the immune response, H ence, agents that can inhibit TNF-alpha may be useful in treating arth ritis and other diseases resulting from uncontrolled inflammation, We now report that the cleavage of heparin by the enzyme heparinase I gen erates sulfated disaccharide (DS) molecules that can inhibit the produ ction of TNF-alpha, Administration of nanogram amounts of the sulfated DS molecules to experimental animals inhibited delayed-type hypersens itivity to a skin sensitizer and arrested the joint swelling of immuno logically induced adjuvant arthritis, Notably, the sulfated DS molecul es showed a bell-shaped dose-response curve in vitro and in vivo: decr eased effects were seen using amounts of the DS molecules higher than optimal, Thus, molecular regulators of inflammation can be released fr om the natural molecule heparin by the action of an enzyme.