The PPARδ agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition

T. Kino, K. C. Rice, G. P. Chrousos

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46 Citations (Scopus)

Abstract

Background: Interleukin-6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator-activated receptor δ (PPARδ), which binds to and is activated by a variety of fatty acids, was recently shown to have anti-inflammatory actions. Materials and methods: We examined the ability of the synthetic PPARδ agonist GW501516 to suppress interleukin-6-induced expression of acute phase proteins in human hepatoma HepG2 cells and rat primary hepatocytes. Results: GW501516 dose-dependently suppressed interleukin-6- induced mRNA expression of the acute phase protein α1-antichymotrypsin in HepG2 cells. The compound also suppressed interleukin-6-induced mRNA expression of α2-acid glycoprotein, β-fibrinogen and α2-macroglobulin in and the secretion of C-reactive protein by rat primary hepatocytes. Depletion of the PPARδ receptor, but not of PPARα or γ, attenuated the suppressive effect of GW501516 on interleukin-6-induced α1- antichymotrypsin mRNA expression, indicating that PPARδ specifically mediated this effect. Since interleukin-6 stimulates the transcriptional activity of the α1-antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPARδ on this promoter. Overexpression of PPARδ enhanced the suppressive effect of GW501516 on STAT3-activated transcriptional activity of the α1-antichymotrypsin promoter, while GW501516 suppressed interleukin-6-induced binding of this transcription factor to this promoter. Conclusions: These findings indicate that agonist-activated PPARδ interferes with interleukin-6-induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPARδ agonists might be useful for the suppression of systemic inflammatory reactions in which IL-6 plays a central role.

Original languageEnglish
Pages (from-to)425-433
Number of pages9
JournalEuropean Journal of Clinical Investigation
Volume37
Issue number5
DOIs
Publication statusPublished - 1 May 2007

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Keywords

  • Inflammation
  • Interleukin-6
  • Peroxisome proliferator-activated receptor δ (PPARδ)
  • Signal transducer and activator of transcription 3 (STAT3)
  • α1-antichymotrypsin

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry

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