D-mannose Dimer Introduced Human Recombinant Interleukin-1α,NEO IL-1α,Exhibits Altered Tissue Distribution in Mice

Abstract

Previous studies have demonstrated that the carbohydrate-introduced recombinant human IL-1α exhibited impairment in both biologic activities in all the experiments in vitro and receptor binding capacity compared with intact IL-1α. However, the glycosylated IL-1α exhibited selective activities in vivo. In this study, we compared the tissue distribution of IL-1αand IL-1α coupled with D-Manα (1–6)Man [Man₂α (1–6)IL-1α] in mice. Mice were injected by intravenous and intraperitoneal routes with 2.0 μg radiolabeled IL-1α. At 1 and 2 h after IP injection, the level of Man₂α (1–6)IL-lα decreased twofold compared with that of IL-1α in kidney. In contrast, at 1 hour after administration, Man₂α (1–6)IL-1α exhibited higher levels than IL-1α in blood, heart, and liver. No significant difference was observed in brain at each time point. IV injection demonstrated that Man₂α (1–6)IL-1α decreased to approximately one-half the level of rhIL-1α in kidney. In contrast, Man₂α (1–6)IL-1α increased twofold over that of IL-1α in liver at 1 h after dosing. These findings are consistent with the result of IP injection. There was no significant difference between IL-1α and glycosylated IL-1α at 4 h after IV administration. These differences in tissue distribution may contribute to the selective activities of glycosylated IL-1α in vivo. The results also suggest that by coupling with mannose dimer, it is possible to develop neocytokines prone to liver distribution.