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Am J Physiol Cell Physiol 292: C209-C215, 2007. First published August 16, 2006; doi:10.1152/ajpcell.00157.2006
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RECEPTORS AND SIGNAL TRANSDUCTION

IL-1 and IL-6 induce hepatocyte plasminogen activator inhibitor-1 expression through independent signaling pathways converging on C/EBP{delta}

Jie Dong,1 Satoshi Fujii,1 Shogo Imagawa,1 Shuichiro Matsumoto,2 Michiaki Matsushita,2 Satoru Todo,2 Hiroyuki Tsutsui,1 and Burton E. Sobel3

Department of 1Cardiovascular Medicine and 2Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and 3Cardiovascular Research Institute of the University of Vermont, Colchester, Vermont

Submitted 5 April 2006 ; accepted in final form 5 August 2006

To elucidate signaling pathways activated by IL-1 and IL-6 that contribute to increased expression of plasminogen activator inhibitor-1 (PAI-1), we studied human hepatoma (HepG2) cells and primary mouse hepatocytes. HepG2 cell PAI-1 mRNA increased in response to IL-1beta, IL-6, and IL-1beta plus IL-6 as shown by real-time PCR. Activity of the transiently transfected PAI-1 promoter (–829 to +36 bp) increased as well. Systematic promoter deletion assays showed that the region from –239 to –210 bp containing a putative CCAAT-enhancer binding protein (C/EBP) binding site was critical. Point mutations in this region abolished the IL-1beta and IL-6 responses. Antibody interference electrophoretic mobility shift assays showed that C/EBP{delta} (but not C/EBP{alpha} or C/EBPbeta) binding and protein were increased by IL-1beta, IL-6, and IL-1beta plus IL-6 in HepG2 cells. IL-1beta and IL-6 increased expression of both PAI-1 mRNA and C/EBP{delta} mRNA in mouse primary hepatocytes as well. Downregulation of C/EBP{delta} induced with small interfering RNA (siRNA) decreased secretion of PAI-1. As judged from results obtained with inhibitors, signal transduction in all three of the mitogen-activated protein kinase pathways was involved in IL-1-inducible PAI-1 expression. By contrast, JAK signaling was responsible for the IL-6-induced inducible expression. Thus IL-1 and IL-6 exert directionally similar effects on PAI-1 expression, but the induction involves distinct signaling pathways with a final common mediator, C/EBP{delta}.

CCAAT-enhancer binding protein; interleukin-1beta; interleukin-6; statins; thrombosis


Address for reprint requests and other correspondence: B. E. Sobel, Cardiovascular Research Institute, Univ. of Vermont, Colchester Research Facility, 208 South Park Dr., Colchester, VT 05446 (e-mail: Burton.Sobel{at}uvm.edu)






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