Heparin decreases the blood clearance of interferon-gamma and increases its activity by limiting the processing of its carboxyl-terminal sequence.

Interferon-gamma (IFN-gamma) binds with high affinity to heparan sulfate and heparin molecules through its carboxyl-terminal domain. In vivo, IFN-gamma is eliminated from the bloodstream with a half-life (t1/2) of 1.1 min, due to binding to heparan sulfate. Unbound IFN-gamma is cleaved rapidly at the carboxyl-terminal side, a process that removes at least 18 amino acids and inactivates the cytokine. When bound to heparin, the plasma clearance of IFN-gamma is decreased greatly (t1/2 = 99 min), and the area under the curve obtained with IFN-gamma alone represented only 15% of that obtained with injected IFN-gamma bound to heparin. Furthermore, the binding of heparin to IFN-gamma limits the extent of its carboxyl-terminal domain degradation to less than 10 amino acids. Importantly, this process increases the cytokine activity by as much as 600%. These data demonstrate that the blood clearance of the cytokine is a non-receptor-mediated process and that in vivo the local concentration of heparan sulfate/heparin-like molecules regulates IFN-gamma activity by a unique mechanism involving a controlled processing of its carboxyl-terminal sequence.