Induction of plasminogen activator inhibitor 1 biosynthesis by hyperthermia.
Hyperthermia is a clinical sign of inflammation and constitutes in itself an adaptive defense mechanism. The fibrinolytic system, a highly regulated proteolytic system, is involved in inflammatory processes. Plasminogen activator inhibitor 1 (PAI-1) is the principal inhibitor of the two activators of the fibrinolytic system: tissue- and urokinase-type PAs (t-PA and u-PA). Our present paper provides the first evidence that hyperthermia can directly induce PAI-1. A moderate heat stress, sufficient to induce heat shock protein 70 mRNA approximately 100-fold, resulted in a two- to three-fold increase in functionally active PAI-1 in the conditioned medium of human HT-1080 fibrosarcoma and Hep G2 hepatoma cells. Exposure of these cells to 42 degrees C led to a similar two-fold and two- to five-fold induction of PAI-1 mRNA expression in HT-1080 and Hep G2 cells, respectively, as has been determined by using both oligo d(T) selected and total RNA preparations. These results suggest that the observed increase in PAI-1 accumulation is due to an induction of PAI-1 biosynthesis. Run-on transcription analysis indicates that the induction of PAI-1 biosynthesis by hyperthermia is mediated by a stimulation of PAI-1 gene transcription. No significant effect of hyperthermia was found on t-PA or u-PA at the level of antigen accumulation, mRNA, and gene transcription in human HT-1080 fibrosarcoma cells. These results point to an additional regulatory mechanism of fibrinolysis in the context of inflammation.
Bergonzelli
G E
GE
Department of Medicine, University Hospital Center, Lausanne, Switzerland.
Kruithof
E K
EK
D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D005354:Fibrosarcoma; D006358:Hot Temperature; D006801:Humans; D008113:Liver Neoplasms; D008969:Molecular Sequence Data; D010960:Plasminogen Activators / Q000378:metabolism; D015849:Plasminogen Inactivators / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator