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 sulfa te and heparin molecules through its carboxyl-terminal domain, In vivo , IFN-gamma is eliminated from the bloodstream with a half-life (t(1/2 )) 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 h eparin, the plasma clearance of IFN-gamma is decreased greatly (t(1/2) = 99 min), and the area under the curve obtained with IFN-gamma alone represented only 15% of that obtained with injected IFN-gamma bound t o heparin, Furthermore, the binding of heparin to IFN-gamma limits the extent of its carboxyl-terminal domain degradation to less than 10 am ino acids. Importantly, this process increases the cytokine activity b y 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 l ocal concentration of heparan sulfate/heparin-like molecules regulates IFN-gamma activity by a unique mechanism involving a controlled proce ssing of its carboxyl-terminal sequence.