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.
Lortat-Jacob
H
H
CNRS URA 1459, Institut Pasteur de Lyon, Avenue T. Garnier, 69365 Lyon cedex 7, France.
Baltzer
F
F
Grimaud
J A
JA
D000818:Animals; D001665:Binding Sites; D001681:Biological Assay; D002460:Cell Line; D006207:Half-Life; D006493:Heparin / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000097:blood* / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000502:physiology
D006493:Heparin; D006497:Heparan Sulfate; D007371:Interferon-gamma; D011994:Recombinant Proteins