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 α. 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 α 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 β 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. © 1996 Wiley‐Liss, Inc.