Non-receptor-mediated tissue localization of human interferon-gamma: role of heparan sulfate/heparin-like molecules.
In addition to its cellular receptor, interferon-gamma (IFN-gamma) displays a high affinity for heparan sulfate. This glycosaminoglycan found in the extracellular matrix and at the surface of some cells was studied here as a possible in vivo binding site for IFN-gamma. For this purpose, rats were injected with [125I]-labelled human IFN-gamma, which does not bind to murine IFN-gamma receptors, but binds to murine heparan sulfate. It was found, first, that [125I]-IFN-gamma does not have equal access to all tissues, accumulating mainly in the spleen, liver and kidney, but not in muscles. Furthermore, [125I]-IFN-gamma was detected by autoradiographic analysis only in restricted areas within tissues, which correlates with the known locations of heparan sulfate. Such local concentrations were detected in the liver sinusoids and in the kidney glomerulus, for example. Heparin bound to [125I]-IFN-gamma was also used to block the heparan sulfate binding site of the cytokine. In this case, blood clearance and tissue accumulation in the liver and spleen were strongly inhibited, while in the kidney the distribution, but not the accumulation, of [125I]-IFN-gamma was affected by the presence of heparin. Kinetic analysis of the binding showed that [125I]-IFN-gamma accumulated in tissues between 5 and 20 min after injection, and was then quickly cleared. Taken together, these data demonstrate that heparan sulfate molecules are involved in blood clearance and in the subsequent tissue targeting, accumulation, and localization of [125I]-IFN-gamma.