IL-1beta down-regulates tissue-type plasminogen activator by up-regulating low-density lipoprotein receptor-related protein in AML 12 cells.
Interleukin-1 (IL-1) regulation of tPA in hepatocytes was studied in mouse hepatocyte line AML12. IL-1 induced transient accumulation of tPA mRNA as high as threefold by 2 h after the start of treatment. The cytokine also induced the mRNA for serum amyloid A, a typical acute-phase protein in mice, with more sustained kinetics in a time-dependent manner. In contrast to the induction of mRNA, tPA activity and protein levels in the harvested medium were dramatically diminished by IL-1. IL-1 stimulated the uptake of (125)I-tPA by AML 12. This uptake was inhibited by 39-kDa receptor-associated protein (RAP), but not by the sugar mannan. These results revealed that low-density lipoprotein receptor-related protein (LRP), which is known to be a receptor for tPA and to be blocked by RAP, was up-regulated by IL-1. We also demonstrated, for the first time, that IL-1 transiently increased the mRNA level of LRP threefold by 30 min after the start of IL-1 treatment of AML 12. The receptor-mediated endocytosis of tPA by hepatocytes may thus play a crucial role in the down-regulation of fibrinolysis during the acute-phase response.
Noguchi
T
T
Department of Nutrition and Physiology, Nihon University College of Bioresource Sciences, Kameino 1866, Fujisawa 252-8516, Japan.
Noguchi
M
M
Masubuchi
H
H
Seki
T
T
Ariga
T
T
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D004705:Endocytosis; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D026563:LDL-Receptor Related Protein-Associated Protein / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
D007375:Interleukin-1; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator