IL-1 and IL-6 induce hepatocyte plasminogen activator inhibitor-1 expression through independent signaling pathways converging on C/EBPδ

Jie Dong, Satoshi Fujii, Shogo Imagawa, Shuichiro Matsumoto, Michiaki Matsushita, Satoru Todo, Hiroyuki Tsutsui, Burton E. Sobel

Research output: Contribution to journalArticle

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Abstract

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-1β, IL-6, and IL-1β 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-1β and IL-6 responses. Antibody interference electrophoretic mobility shift assays showed that C/EBPδ (but not C/EBPα or C/EBPβ) binding and protein were increased by IL-1β, IL-6, and IL-1β plus IL-6 in HepG2 cells. IL-1β and IL-6 increased expression of both PAI-1 mRNA and C/EBPδ mRNA in mouse primary hepatocytes as well. Downregulation of C/EBPδ 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/EBPδ.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Volume292
Issue number1
DOIs
Publication statusPublished - Jan 1 2007

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CCAAT-Enhancer-Binding Proteins
Plasminogen Activator Inhibitor 1
Interleukin-1
Hepatocytes
Interleukin-6
Hep G2 Cells
Protein Binding
Messenger RNA
Electrophoretic Mobility Shift Assay
Mitogen-Activated Protein Kinases
Point Mutation
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Hepatocellular Carcinoma
Signal Transduction
Carrier Proteins
Down-Regulation
Binding Sites

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

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IL-1 and IL-6 induce hepatocyte plasminogen activator inhibitor-1 expression through independent signaling pathways converging on C/EBPδ. / Dong, Jie; Fujii, Satoshi; Imagawa, Shogo; Matsumoto, Shuichiro; Matsushita, Michiaki; Todo, Satoru; Tsutsui, Hiroyuki; Sobel, Burton E.

In: American Journal of Physiology - Cell Physiology, Vol. 292, No. 1, 01.01.2007.

Research output: Contribution to journalArticle

Dong, Jie ; Fujii, Satoshi ; Imagawa, Shogo ; Matsumoto, Shuichiro ; Matsushita, Michiaki ; Todo, Satoru ; Tsutsui, Hiroyuki ; Sobel, Burton E. / IL-1 and IL-6 induce hepatocyte plasminogen activator inhibitor-1 expression through independent signaling pathways converging on C/EBPδ. In: American Journal of Physiology - Cell Physiology. 2007 ; Vol. 292, No. 1.
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AB - 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-1β, IL-6, and IL-1β 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-1β and IL-6 responses. Antibody interference electrophoretic mobility shift assays showed that C/EBPδ (but not C/EBPα or C/EBPβ) binding and protein were increased by IL-1β, IL-6, and IL-1β plus IL-6 in HepG2 cells. IL-1β and IL-6 increased expression of both PAI-1 mRNA and C/EBPδ mRNA in mouse primary hepatocytes as well. Downregulation of C/EBPδ 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/EBPδ.

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