Interleukin-10 suppresses tissue factor expression in lipopolysaccharide- stimulated macrophages via inhibition of Egr-1 and a serum response element/MEK-ERK1/2 pathway

Motohiro Kamimura, Christiane Viedt, Alexander Dalpke, Michael E. Rosenfeld, Nigel Mackman, David Cohen, Erwin Blessing, Michael Preusch, Christian M. Weber, Jörg Kreuzer, Hugo A. Katus, Florian Bea

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Atherosclerosis is considered to be an inflammatory disease. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play an essential role in thrombus formation after atherosclerotic plaque rupture. Recent studies suggest that the antiinflammatory cytokine interleukin-10 (IL-10) has many antiatherosclerotic properties. Therefore, the effects of IL-10 on TF expression in response to inflammation were investigated. Mouse macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of IL-10. Pretreatment with IL-10 resulted in a 50% decrease in TF mRNA expression and TF promoter activity. Binding of early growth response gene-1 (Egr-1) to the consensus DNA sequence, a key transcriptional activator of TF expression in response to inflammation, and the expression of Egr-1 mRNA were also inhibited by IL-10. This inhibition was independent of the induction of suppressor of cytokine signaling protein-3 by IL-10. Macrophages that had been transfected with luciferase reporter constructs containing the murine Egr-1 5′-flanking sequence exhibited reduced reporter gene activity in response to LPS stimulation with IL-10 pretreatment. Studies with deletion constructs of the Egr-1 promoter identified the proximal serum response element SRE3 as a potential regulatory site for the IL-10 mediated suppression of Egr-1 expression. Furthermore, activation of the upstream signal-transduction elements, such as mitogen-activated protein kinase kinase (MEK) 1/2, extracellular signal-regulated kinase 1/2, and Elk-1 were also inhibited by IL-10 pretreatment. Taken together, these results demonstrate a pathway for the IL-10 mediated inhibition of TF expression during inflammation and may explain the antiatherosclerotic effects of IL-10.

Original languageEnglish (US)
Pages (from-to)305-313
Number of pages9
JournalCirculation Research
Volume97
Issue number4
DOIs
StatePublished - Aug 19 2005

Fingerprint

Serum Response Element
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Thromboplastin
Interleukin-10
Lipopolysaccharides
Macrophages
Growth
Genes
Atherosclerotic Plaques
Inflammation
MAP Kinase Kinase 1
Messenger RNA
Mitogen-Activated Protein Kinase 3
5' Flanking Region
Mitogen-Activated Protein Kinase 1
Consensus Sequence
Luciferases
Reporter Genes
Rupture

Keywords

  • Atherosclerosis
  • Early growth response gene
  • Interleukin
  • Macrophages
  • Tissue factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Interleukin-10 suppresses tissue factor expression in lipopolysaccharide- stimulated macrophages via inhibition of Egr-1 and a serum response element/MEK-ERK1/2 pathway. / Kamimura, Motohiro; Viedt, Christiane; Dalpke, Alexander; Rosenfeld, Michael E.; Mackman, Nigel; Cohen, David; Blessing, Erwin; Preusch, Michael; Weber, Christian M.; Kreuzer, Jörg; Katus, Hugo A.; Bea, Florian.

In: Circulation Research, Vol. 97, No. 4, 19.08.2005, p. 305-313.

Research output: Contribution to journalArticle

Kamimura, M, Viedt, C, Dalpke, A, Rosenfeld, ME, Mackman, N, Cohen, D, Blessing, E, Preusch, M, Weber, CM, Kreuzer, J, Katus, HA & Bea, F 2005, 'Interleukin-10 suppresses tissue factor expression in lipopolysaccharide- stimulated macrophages via inhibition of Egr-1 and a serum response element/MEK-ERK1/2 pathway', Circulation Research, vol. 97, no. 4, pp. 305-313. https://doi.org/10.1161/01.RES.0000177893.24574.13
Kamimura, Motohiro ; Viedt, Christiane ; Dalpke, Alexander ; Rosenfeld, Michael E. ; Mackman, Nigel ; Cohen, David ; Blessing, Erwin ; Preusch, Michael ; Weber, Christian M. ; Kreuzer, Jörg ; Katus, Hugo A. ; Bea, Florian. / Interleukin-10 suppresses tissue factor expression in lipopolysaccharide- stimulated macrophages via inhibition of Egr-1 and a serum response element/MEK-ERK1/2 pathway. In: Circulation Research. 2005 ; Vol. 97, No. 4. pp. 305-313.
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abstract = "Atherosclerosis is considered to be an inflammatory disease. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play an essential role in thrombus formation after atherosclerotic plaque rupture. Recent studies suggest that the antiinflammatory cytokine interleukin-10 (IL-10) has many antiatherosclerotic properties. Therefore, the effects of IL-10 on TF expression in response to inflammation were investigated. Mouse macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of IL-10. Pretreatment with IL-10 resulted in a 50{\%} decrease in TF mRNA expression and TF promoter activity. Binding of early growth response gene-1 (Egr-1) to the consensus DNA sequence, a key transcriptional activator of TF expression in response to inflammation, and the expression of Egr-1 mRNA were also inhibited by IL-10. This inhibition was independent of the induction of suppressor of cytokine signaling protein-3 by IL-10. Macrophages that had been transfected with luciferase reporter constructs containing the murine Egr-1 5′-flanking sequence exhibited reduced reporter gene activity in response to LPS stimulation with IL-10 pretreatment. Studies with deletion constructs of the Egr-1 promoter identified the proximal serum response element SRE3 as a potential regulatory site for the IL-10 mediated suppression of Egr-1 expression. Furthermore, activation of the upstream signal-transduction elements, such as mitogen-activated protein kinase kinase (MEK) 1/2, extracellular signal-regulated kinase 1/2, and Elk-1 were also inhibited by IL-10 pretreatment. Taken together, these results demonstrate a pathway for the IL-10 mediated inhibition of TF expression during inflammation and may explain the antiatherosclerotic effects of IL-10.",
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AU - Mackman, Nigel

AU - Cohen, David

AU - Blessing, Erwin

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