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Inhibition by pentoxifylline of extracellular signal‐regulated kinase activation by platelet‐derived growth factor in hepatic stellate cells
Author(s) -
Pinzani Massimo,
Marra Fabio,
Caligiuri Alessandra,
DeFranco Raffaella,
Gentilini Alessandra,
Failli Paola,
Gentilini Paolo
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb16012.x
Subject(s) - platelet derived growth factor receptor , extracellular , growth factor , platelet derived growth factor , pentoxifylline , mapk/erk pathway , hepatic stellate cell , intracellular , extracellular matrix , microbiology and biotechnology , autophosphorylation , signal transduction , biology , kinase , chemistry , endocrinology , biochemistry , protein kinase a , receptor , pharmacology
1 It has been proposed that pentoxifylline (PTF) acts an antifibrogenic agent by reducing the synthesis of extracellular matrix components, and this possibility has been confirmed in animal models of hepatic fibrosis. In this study the effects of PTF on the proliferation of extracellular matrix producing cells induced by platelet‐derived growth factor (PDGF) were evaluated. The study was performed on hepatic stellate cells, currently indicated as the major source of extracellular matrix in fibrotic liver. 2 PTF caused a dose‐dependent reduction of PDGF‐induced mitogenesis with an IC 50 of 170 μ m , identical to the EC 50 for the increase in intracellular cyclic AMP levels. Preincubation with PTF did not affect either PDGF‐receptor autophosphorylation or phosphotidylinositol 3‐kinase activity, whereas it markedly reduced PDGF‐stimulated extracellular signal‐regulated kinase (ERK) activity and ERK isoform phosphorylation. PTF also reduced PDGF‐induced c‐fos mRNA expression, which is dependent on activation of the RAS/ERK pathway. In addition, the PDGF‐induced increase in cytsolic‐free calcium was almost completely prevented by pretreating the cells with PTF. 3 The results of the present study indicate that PTF, in addition to its effect on collagen deposition and degradation, may exert an antifibrogenic effect by reducing the PDGF‐induced proliferation of extracellular matrix producing cells. This effect appears to be mediated by a reduction of PDGF‐stimulated ERK activity as well as of other intracellular signalling pathways such as the PDGF‐induced elevation of cytosolic‐free calcium.