Interleukin-1 beta up-regulates the plasminogen activator/plasmin system in human mesangial cells.
The plasminogen activators (PA), which are regulated by their specific inhibitor, PAI-1, convert the zymogen plasminogen to plasmin, a protease involved in fibrinolysis and extracellular matrix turnover. Interleukin 1 beta (IL-1) is a key cytokine released from infiltrating monocytes/macrophages during the initial stages of glomerular injury. We investigated the effects of IL-1 on the production of tissue-type plasminogen activator (t-PA), urokinase (u-PA) and PAI-1 by glomerular cells. IL-1 significantly increased the synthesis of t-PA by mesangial cells and glomerular epithelial cells (P < 0.005 for both cell types), while u-PA production was unaltered. PAI-1 in mesangial cell supernatants was significantly lower when cultured in the presence of IL-1 (p < 0.008), and the synthesis decreased in a time and dose dependent manner. The effects of IL-1 were eliminated by anti-IL-1 neutralizing antibodies. The PAI-1 sequestered in the extracellular matrix of mesangial cells was also decreased. No significant change in PAI-1 synthesis by epithelial cells was observed with exogenous IL-1. Northern blot analysis paralleled the protein results, demonstrating an increase in t-PA and a decrease in PAI-1 mRNA of mesangial cells after 6 and 24 hours stimulation with 10 U/ml IL-1. These studies suggest a role for IL-1 in regulating localized proteolysis by mesangial cells during acute inflammation.
Wilson
H M
HM
Department of Molecular and Cell Biology, University of Aberdeen, Scotland, United Kingdom.
Haites
N E
NE
Reid
F J
FJ
Booth
N A
NA
D000941:Antigens / Q000235:genetics; D015152:Blotting, Northern; D002478:Cells, Cultured / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015342:DNA Probes; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005341:Fibrinolysin / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
D000941:Antigens; D016861:Cyclooxygenase Inhibitors; D015342:DNA Probes; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin