Modulation of mRNA levels for urinary- and tissue-type plasminogen activator and plasminogen activator inhibitors 1 and 2 in human fibroblasts by interleukin 1.
Plasminogen activators and their inhibitors are thought to play an important role in the regulation of a variety of pathologic processes including inflammation and wound healing. IL-1 is one inflammatory mediator which has been shown to increase release of plasminogen activator (PA) Ag and activity by mesenchymal cells such as chondrocytes and synoviocytes. We have found that rIL-1 beta induces a rapid and significant accumulation of both tissue-and urinary-type plasminogen activator (t-PA and u-PA) mRNA and type 1 and 2 plasminogen activator inhibitor (PAI-1 and PAI-2) mRNA in MRC-5 fetal lung fibroblasts. An SV40 transformed fibroblast cell line, XP12RO, showed an identical response of PAI-1 and t-PA message levels but revealed no change in PAI-2 or u-PA mRNA levels with rIL-1 beta stimulation. Treatment with the transcriptional inhibitor actinomycin D blocked accumulation of t-PA, u-PA, PAI-1, and PAI-2 mRNA, suggesting that RNA synthesis is required for accumulation of all four transcripts. Cycloheximide (CHX) treatment altered the rate of PAI-1 and t-PA mRNA accumulation, but both were able to increase in the absence of protein synthesis. CHX blocked the rIL-1 beta-induced increase in PAI-2 mRNA levels normally observed at 8 h, indicating that protein synthesis is required for this response to IL-1. The increase in u-PA message level was augmented in a synergistic fashion by CHX. These data for PAI-2 and u-PA provide evidence for short-lived proteins which act either to modulate transcription of these genes or regulate mRNA stability. Thus plasminogen activators and their inhibitors are regulated in a positive and complex fashion in the fibroblast by IL-1, suggesting an important role for these molecules and this cell type in the response to inflammation.
Michel
J B
JB
Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston 02114.
Quertermous
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D002461:Cell Line, Transformed; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006023:Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D010960:Plasminogen Activators / Q000096:biosynthesis / Q000652:urine*; D015849:Plasminogen Inactivators; D012333:RNA, Messenger / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000378:metabolism*
D006023:Glycoproteins; D007375:Interleukin-1; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D011994:Recombinant Proteins; D003609:Dactinomycin; D003513:Cycloheximide; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator