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Regulation of plasminogen gene expression by interleukin-6
GR Jenkins, D Seiffert, RJ Parmer and LA Miles
Department of Vascular Biology (VB-1), The Scripps Research Institute, La
Jolla, CA 92037, USA.
Plasmin, the primary fibrinolytic enzyme, has a broad substrate spectrum
and participates in other biological processes dependent upon proteolytic
activity. Consequently, plasmin activity is tightly regulated by
plasminogen activators and protease inhibitors. In this study, we examined
whether regulation of plasminogen gene expression also might provide a new
mechanism for controlling this system. We examined the effects of
recombinant human interleukin-6 (rhIL-6), a pleiotropic cytokine, on
plasminogen mRNA expression in primary murine hepatocytes and Hep3B human
hepatoma cells. In primary hepatocytes, rhIL-6 and hydrocortisone
separately increased plasminogen mRNA expression, but hydrocortisone did
not markedly enhance the response to rhIL-6. Hep3B hepatoma cells exhibited
more modest responses to rhIL-6. We used the polymerase chain reaction to
amplify a 1,067-bp fragment of the human plasminogen promoter/5' flanking
region. This fragment was cloned upstream of a luciferase reporter gene.
Hep3B cells transiently transfected with this construct provided
approximately 100-fold higher luciferase activity compared to cells
transfected with control plasmids, and luciferase activity was increased
approximately 4.5-fold when these cells were treated with rhIL-6.
Furthermore, mice injected with rhIL-6 exhibited increases in hepatic
plasminogen mRNA. Circulating plasminogen levels were significantly higher
in the mice injected with rhIL-6 compared to mice injected with saline.
Mice injected with lipopolysaccharide (an inducer of IL-6 in vivo) also
showed increased hepatic plasminogen mRNA. Thus, plasminogen gene
expression can be modulated by rhIL-6, suggesting a new mechanism for
regulating biological systems that use plasmin.
Volume 89,
Issue 7,
pp. 2394-2403,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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