Octreotide modulates the effects on fibrosis of TNF-α, TGF-β and PDGF in activated rat hepatic stellate cells

Background and aims: 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 alpha 1-procollagen (alpha 1-PROC) production in TNF alpha, TGF-beta 1 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 alpha 1-PROC production. Interestingly, it enhanced PDGF-induced HSC proliferation but inhibited PDGF and TGF beta 1 dependent expression of alpha 1-PROC, while an opposite effect was observed in TNF alpha-induced cell proliferation and collagen production. PTP inhibition reversed the inhibitory effect of octreotide on alpha 1-PROC, but potentiated its effect on PDGF and TGF beta 1 dependent alpha 1-PROC production. Finally, STP inhibition profoundly inhibited alpha 1-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. (C) 2013 Elsevier B.V. All rights reserved.