Inhibition of transforming growth factor β signaling by halofuginone as a modality for pancreas fibrosis prevention

Orit Zion, Olga Genin, Norifumi Kawada, Katsutoshi Yoshizato, Suzy Roffe, Arnon Nagler, Juan L. Iovanna, Orna Halevy, Mark Pines

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVES: Chronic pancreatitis is characterized by inflammation and fibrosis. We evaluated the efficacy of halofuginone, an inhibitor of collagen synthesis and myofibroblast activation, in preventing cerulein-induced pancreas fibrosis. METHODS: Collagen synthesis was evaluated by in situ hybridization and staining. Levels of prolyl 4-hydroxylase β (P4Hβ), cytoglobin/stellate cell activation-associated protein (Cygb/STAP), transgelin, tissue inhibitors of metalloproteinases, serum response factor, transforming growth factor β (TGFβ), Smad3, and pancreatitis-associated protein 1 (PAP-1) were determined by immunohistochemistry. Metalloproteinase activity was evaluated by zymography. RESULTS: Halofuginone prevented cerulein-dependent increase in collagen synthesis, collagen cross-linking enzyme P4Hβ, Cygb/STAP, and tissue inhibitors of metalloproteinase 2. Halofuginone did not affect TGFβ levels in cerulein-treated mice but inhibited serum response factor synthesis and Smad3 phosphorylation. In culture, halofuginone inhibited pancreatic stellate cell (PSC) proliferation and TGFβ-dependent increase in Cygb/STAP and transgelin synthesis and metalloproteinase 2 activity. Halofuginone increased c-Jun N-terminal kinase phosphorylation in PSCs derived from cerulein-treated mice. Halofuginone prevented the increase in acinar cell proliferation and further increased the cerulein-dependent PAP-1 synthesis. CONCLUSIONS: Halofuginone inhibits Smad3 phosphorylation and increases c-Jun N-terminal kinase phosphorylation, leading to the inhibition of PSC activation and consequent prevention of fibrosis. Halofuginone increased the synthesis of PAP-1, which further reduces pancreas fibrosis. Thus, halofuginone might serve as a novel therapy for pancreas fibrosis.

Original languageEnglish
Pages (from-to)427-435
Number of pages9
JournalPancreas
Volume38
Issue number4
DOIs
StatePublished - May 2009
Externally publishedYes

Keywords

  • Collagen
  • Cytoglobin
  • Myofibroblasts
  • Pancreatic stellate cells
  • Smad
  • Transgelin

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