Pentoxifylline modulates intracellular signalling of TGF-β in cultured human peritoneal mesothelial cells: Implications for prevention of encapsulating peritoneal sclerosis

Background. Peritoneal matrix accumulation is a major characteristic of encapsulating peritoneal sclerosis (EPS), which is a serious complication in long-term peritoneal dialysis (PD) patients. We reported previously that TGF-β stimulates collagen gene expression in cultured HPMC, and is attenuated by pentoxifylline (PTX). The SMAD family and the mitogen-activated protein kinase (MAPK) (ERK1/2, JNK and p38^HOG) pathways have been shown to participate in TGF-β signalling. However, how PTX modulates the intracellular signalling downstream to TGF-β remains undetermined in HPMC. In this study, we explored these signalling pathways in HPMC, and investigated the molecular mechanisms involved in the inhibitory effects of PTX on TGF-β-induced collagen gene expression in HPMC. Methods. HPMC was cultured from human omentum by an enzyme digestion method. The expression of collagen α1(I) mRNA was determined by northern blotting, while the SMAD proteins and the MAPK kinase activity were determined by western blotting. Results. TGF-β-stimulated collagen α1(I) mRNA expression of HPMC was inhibited by PTX. The Smad2, ERK1/2 and p38^HOG pathways were activated in response to TGF-β. However, TGF-β displayed no activation of the JNK pathway in HPMC. The addition of PD98059 and SB203580, which blocked the activation of ERK1/2 and p38^HOG, respectively, suppressed the TGF-β-induced collagen α1(I) mRNA expression. At a concentration (300 μg/ml) that inhibited the collagen gene expression, PTX suppressed the ERK1/2 and p38^HOG activation by TGF-β. In contrast, PTX had no effect on the TGF-β-induced activation of Smad2, under the same concentration. Conclusion. PTX inhibits the TGF-β-induced collagen gene expression in HPMC through modulating the ERK1/2 and p38^HOG pathways. Our study of PTX may provide the therapeutic basis for clinical applications in the prevention of EPS.