Interleukin-1 induction of type-1 plasminogen activator inhibitor (PAI-1) gene expression in the mouse hepatocyte line, AML 12.
Type-1 plasminogen activator inhibitor (PAI-1), the major regulator of fibrinolysis, is an important component of the acute phase (AP) response, the coordinated systemic reaction of an organism to tissue injury. As part of a combined in vivo and in vitro study of AP regulation of PAI-1 gene expression in murine hepatocytes, we have characterized the cytokine regulation of PAI-1 gene expression in AML 12 cells, an established line of normal hepatocytes derived from an adult transgenic mouse overexpressing transforming growth factor alpha. Interleukin (IL)-1 caused a rapid and transient 4-fold increase in PAI-1 mRNA that was maximal at 1 h. Half-maximal induction by IL-1 was obtained at 50 U/ml and maximal effects were seen at approximately 500 U/ml. Tumor necrosis factor alpha induced PAI-1 mRNA accumulation with the same magnitude and time course as IL-1, and was not additive with IL-1. IL-6 and dexamethasone alone had no effect on PAI-1 mRNA accumulation and did not enhance the effect of IL-1. Transforming growth factor beta caused a sustained 5- to 7-fold increase in the accumulation of PAI-1 mRNA that was maximal after 2 to 4 h. The IL-1 induction of PAI-1 was inhibited by actinomycin D, but not by cycloheximide. Nuclear run-on studies demonstrated that IL-1 induced a rapid and transient increase in PAI-1 gene transcription that was maximal at 30 min. IL-1 did not stabilize PAI-1 mRNA, and might, in fact, accelerate its rate of decay. These data demonstrate that IL-1, a potent mediator of AP response, induces the accumulation of PAI-1 mRNA in murine hepatocytes, at least in part, by rapidly and transiently increasing the rate of transcription of the PAI-1 gene.
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Department of Human Genetics, The University of Michigan Medical School, Ann Arbor 48109-0618, USA.
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D000210:Acute-Phase Reaction; D000818:Animals; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007375:Interleukin-1 / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide