Pentoxifylline inhibits hepatic stellate cells proliferation via the Raf/ERK pathway

Abstract

Pentoxifylline (PTX), which is a xanthine derivative, is a well-known suppressor of tumor necrosis factor-alpha (TNF-alpha) production in inflammatory cells and has also been shown to inhibit collagen synthesis in hepatic stellate cells (HSCs) in vitro. The present study aimed to evaluate the effects of PTX on proliferation in HSCs as mediated by the Raf/MEK/extracellular-signal-regulated kinase (ERK) signaling pathway. The rat hepatic stellate cell line T6 and activated primary rat HSCs were used in this study. The proliferation rate of the cells treated with 1 mM PTX significantly decreased compared with that of the control in T6 cells (78.3 ± 6.03% at 12 h, 61.0 ± 7.55% at 24 h, and 44.7 ± 2.08% at 48 h, p < 0.05). PTX (1 mM) also decreased the fraction of the HSC population in the S and G2/M-phases of the cell cycle in primary activated rat HSCs. The Raf-1 inhibitor GW5074 and the ERK inhibitor U0126 had inhibitory effects that were similar to those of PTX on HSC proliferation. In addition, PTX inhibited the phosphorylation of Raf-1 (p-Raf-1) and ERK (p-ERK) in a dose- and time-dependent manner in HSCs. These data provide evidence that PTX suppresses HSC proliferation via the Raf/MEK/ERK pathway.