title: Heme oxygenase-1 inhibits the proliferation of pancreatic stellate cells by repression of the extracellular signal-regulated kinase1/2 pathway.
abstract: Activation of pancreatic stellate cells (PSCs) is the key process in the development of pancreatic fibrosis, a common feature of chronic pancreatitis and pancreatic cancer. In recent studies, curcumin has been shown to inhibit PSC proliferation via an extracellular signal-regulated kinase (ERK)1/2-dependent mechanism. In addition, curcumin is a potent inducer of the cytoprotective enzyme heme oxygenase-1 (HO-1) in other cell types. Therefore, the aims of this study were to 1) characterize the effect of curcumin on HO-1 gene expression in PSCs, 2) explore whether HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation, and 3) clarify the involvement of the mitogen-activated protein kinase (MAPK) family in this context. Cultured rat PSCs were incubated with curcumin and assessed for HO-1 up-regulation by Northern blot analysis, immunoblotting, and activity assays. The effect of HO-1 on platelet-derived growth factor (PDGF)-induced PSC proliferation and MAPK activation was determined by immunoblotting, cell proliferation assays, and cell count analyses. Curcumin induced HO-1 gene expression in PSCs in a time- and dose-dependent manner and inhibited PDGF-mediated ERK1/2 phosphorylation and PSC proliferation. These effects were blocked by treatment of PSCs with tin protoporphyrin IX, an HO inhibitor, or transfection of HO-1 small interfering RNA. Our data provide evidence that HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation. Therefore, therapeutic up-regulation of HO-1 could represent a mode for inhibition of PSC proliferation and thus may provide a novel strategy in the prevention of pancreatic fibrosis.
authors.affiliation: Department of Anesthesiology, University Medical Center, Freiburg, Germany.
authors.forename: Christian I
authors.initials: CI
authors.lastname: Schwer
authors.forename: Aida M
authors.initials: AM
authors.lastname: Guerrero
authors.forename: Matjaz
authors.initials: M
authors.lastname: Humar
authors.forename: Martin
authors.initials: M
authors.lastname: Roesslein
authors.forename: Ulrich
authors.initials: U
authors.lastname: Goebel
authors.forename: Patrick
authors.initials: P
authors.lastname: Stoll
authors.forename: Klaus K
authors.initials: KK
authors.lastname: Geiger
authors.forename: Benedikt H J
authors.initials: BH
authors.lastname: Pannen
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoetzel
authors.forename: Rene
authors.initials: R
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D010982:Platelet-Derived Growth Factor; D051547:Heme Oxygenase-1; D048052:Mitogen-Activated Protein Kinase 3; D003474:Curcumin