title: Octreotide modulates the effects on fibrosis of TNF-α, TGF-β and PDGF in activated rat hepatic stellate cells.
abstract: OBJECTIVE
  Somatostatin and its analogs may influence hepatic fibrosis interfering through several mechanisms. The aim of this study was to investigate the effect of octreotide on cytokine activated hepatic stellate cells (HSC).
  
  
  METHODS
  Primary HSCs were isolated from rats and were cultured on plastic for activation. Expression of somatostatin receptors (SSTR) was investigated in cultured HSCs by immunofluorescence and western blot. The effect of octreotide on cellular proliferation was studied with the MTT assay and western blot for α1-procollagen (α1-PROC) production in TNFα, TGF-β1 or PDGF treated HSCs. Phosphotyrosine (PTP) and phosphoserine-phosphothreonine (STP) phosphatases inhibition was performed with sodium orthovanadate and okadaic acid respectively.
  
  
  RESULTS
  Activated HSC express SSTR subtypes 1, 2A, 2B, 3 and 4 and their expression is enhanced by further HSC activation. Octreotide did not have an effect on HSC proliferation but inhibited plastic induced α1-PROC production. Interestingly, it enhanced PDGF-induced HSC proliferation but inhibited PDGF and TGFβ1 dependent expression of α1-PROC, while an opposite effect was observed in TNFα-induced cell proliferation and collagen production. PTP inhibition reversed the inhibitory effect of octreotide on α1-PROC, but potentiated its effect on PDGF and TGFβ1 dependent α1-PROC production. Finally, STP inhibition profoundly inhibited α1-PROC expression in all cases suggesting that both STP and PTP phosphatases are important regulators of pro-fibrotic mechanisms.
  
  
  CONCLUSIONS
  The net effect of octreotide on HSCs and therefore liver fibrosis is subject to the cytokine microenvironment of these cells. This effect is modulated by PTPs and STPs inhibition. Especially in the case of STPs their profibrotic effects could be an interesting new therapeutic target in liver fibrosis.
authors.affiliation: Liver Research Laboratory, Medical School, University of Crete, Voutes 71003 Crete, Greece.
authors.forename: Stefanos
authors.initials: S
authors.lastname: Klironomos
authors.affiliation: Liver Research Laboratory, Medical School, University of Crete, Voutes 71003 Crete, Greece; Laboratory of Experimental Endocrinology, Medical School, University of Crete, Voutes 71003 Crete, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Notas
authors.affiliation: Liver Research Laboratory, Medical School, University of Crete, Voutes 71003 Crete, Greece.
authors.forename: Ourania
authors.initials: O
authors.lastname: Sfakianaki
authors.affiliation: Laboratory of Experimental Endocrinology, Medical School, University of Crete, Voutes 71003 Crete, Greece.
authors.forename: Foteini
authors.initials: F
authors.lastname: Kiagiadaki
authors.affiliation: Liver Research Laboratory, Medical School, University of Crete, Voutes 71003 Crete, Greece.
authors.forename: Costas
authors.initials: C
authors.lastname: Xidakis
authors.affiliation: Liver Research Laboratory, Medical School, University of Crete, Voutes 71003 Crete, Greece. Electronic address: kouroum@med.uoc.gr.
authors.forename: Elias
authors.initials: E
authors.lastname: Kouroumalis
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008297:Male; D015282:Octreotide / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D017481:Receptors, Somatostatin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D017027:Protein Tyrosine Phosphatases; D015282:Octreotide
keywords: Fibrosis; Hepatic stellate cells; Procollagen; Somatostatin; Somatostatin receptors