Ligands of peroxisome proliferator-activated receptor-γ block activation of pancreatic stellate cells

Atsushi Masamune, Kazuhiro Kikuta, Masahiro Satoh, Yoshitaka Sakai, Akihiko Satoh, Tooru Shimosegawa

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Peroxisome proliferator-activated receptor γ (PPAR-γ) is a ligand-activated transcription factor which controls growth, differentiation, and inflammation in different tissues. Roles of PPAR-γ activation in PSCs are poorly characterized. Here we examined the effects of PPAR-γ ligands on the key parameters of PSC activation. PSCs were isolated from rat pancreas tissue, and used in their culture-activated, myofibroblast-like phenotype. Activation of PPAR-γ was induced with 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or with troglitazone. Expression of PPAR-γ was predominantly localized in the nuclei, and PPAR-γ was transcriptionally active after ligand stimulation. PPAR-γ ligands inhibited platelet-derived growth factor-induced proliferation. This effect was associated with inhibition of cell cycle progression beyond the G1 phase. PPAR-γ ligands decreased α-smooth muscle actin protein expression and α1(I) procollagen and prolyl 4-hydroxylase(α) mRNA levels. Activation of PPAR-γ also resulted in the inhibition of inducible monocyte chemoattractant protein-1 expression. 15d-PGJ2, but not troglitazone, inhibited the degradation of IκB-α and consequent NF-κB activation. In conclusion, activation of PPAR-γ inhibited profibrogenic and proinflammatory actions in activated PSCs, suggesting a potential application of PPAR-γ ligands in the treatment of pancreatic fibrosis and inflammation.

Original languageEnglish
Pages (from-to)141-147
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number1
DOIs
Publication statusPublished - 2002 Jan 4

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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