Seiji Takemoto1, Makiya Nishikawa, Yoshinobu Takakura. 1. Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Abstract
PURPOSE: To investigate the in vivo pharmacokinetics and uptake mechanisms of recombinant mouse heat shock protein 70 (Hsp70) by hepatocytes in mice. METHODS: The tissue distribution and intrahepatic localization of Hsp70 were determined after an intravenous injection of 111In-Hsp70 (111In-Hsp70) into mice. Ligands of CD91 or scavenger receptors were injected prior to Hsp70 to examine the involvement of these molecules on the distribution of 111In-Hsp70. The uptake of 111In-Hsp70 by primary mouse hepatocytes was also examined. RESULTS: After intravenous injection, 111In-Hsp70 was rapidly eliminated from the circulation and taken up mainly by the liver. The hepatic uptake was significantly inhibited by preinjection of ligands for CD91 or scavenger receptors. The separation of liver-constituting cells revealed a major contribution of hepatocytes to the overall hepatic uptake of 111In-Hsp70. The uptake of 111In-Hsp70 by cultured hepatocytes was inhibited by a CD91 ligand or anti-CD91 anibody. In addition, after subcutaneous injection, 111In-Hsp70 gradually disappeared from the injection site and accumulated in primary lymph nodes. CONCLUSIONS: These results indicate for the first time that intravenous Hsp70 is, at least partially, recognized by CD91 and eliminated by hepatocytes, whereas subcutaneous Hsp70 is efficiently delivered to regional lymph nodes.
PURPOSE: To investigate the in vivo pharmacokinetics and uptake mechanisms of recombinant mouseheat shock protein 70 (Hsp70) by hepatocytes in mice. METHODS: The tissue distribution and intrahepatic localization of Hsp70 were determined after an intravenous injection of 111In-Hsp70 (111In-Hsp70) into mice. Ligands of CD91 or scavenger receptors were injected prior to Hsp70 to examine the involvement of these molecules on the distribution of 111In-Hsp70. The uptake of 111In-Hsp70 by primary mouse hepatocytes was also examined. RESULTS: After intravenous injection, 111In-Hsp70 was rapidly eliminated from the circulation and taken up mainly by the liver. The hepatic uptake was significantly inhibited by preinjection of ligands for CD91 or scavenger receptors. The separation of liver-constituting cells revealed a major contribution of hepatocytes to the overall hepatic uptake of 111In-Hsp70. The uptake of 111In-Hsp70 by cultured hepatocytes was inhibited by a CD91 ligand or anti-CD91 anibody. In addition, after subcutaneous injection, 111In-Hsp70 gradually disappeared from the injection site and accumulated in primary lymph nodes. CONCLUSIONS: These results indicate for the first time that intravenous Hsp70 is, at least partially, recognized by CD91 and eliminated by hepatocytes, whereas subcutaneous Hsp70 is efficiently delivered to regional lymph nodes.
Authors: Y Moroi; M Mayhew; J Trcka; M H Hoe; Y Takechi; F U Hartl; J E Rothman; A N Houghton Journal: Proc Natl Acad Sci U S A Date: 2000-03-28 Impact factor: 11.205
Authors: Thomas Kirkegaard; James Gray; David A Priestman; Kerri-Lee Wallom; Jennifer Atkins; Ole Dines Olsen; Alexander Klein; Svetlana Drndarski; Nikolaj H T Petersen; Linda Ingemann; David A Smith; Lauren Morris; Claus Bornæs; Signe Humle Jørgensen; Ian Williams; Anders Hinsby; Christoph Arenz; David Begley; Marja Jäättelä; Frances M Platt Journal: Sci Transl Med Date: 2016-09-07 Impact factor: 17.956