Pentoxifylline Modulates Intracellular Signaling of TGF-ß in Cultured Human Peritoneal Mesothelial Cells

Background Peritoneal matrix accumulation is characteristics of encapsulating peritoneal sclerosis (EPS), which is a serious complication in long-term peritoneal dialysis (PD) patients. We previously (Kidney Int 2000,Jun) had reported that TGF-ß stimulates expression of type I and III collagen mRNA in cultured HPMC, and was attenuated by pentoxifylline (PTX). However, this inhibitory mechanism remains undetermined. The SMAD family and the mitogen-activated protein kinase (MAPK) (ERK1/2, JNK and p38 HOG)pathways have been shown to participate in TGF-ß signaling. In this study, we investigated the molecular mechanisms involved in the inhibitory effects of PTX on TGF-ß induced collagen gene expression in HPMC. Methods. HPMC was cultured from human omentum by an enzyme digestion method. Expression of collagen α1(I) mRNA was determined by northern blotting. The SMAD proteins and the MAPK kinase activity were determined by Western blotting. Results. TGF-ß stimulated collagen α1(I) mRNA expression of HPMC was inhibited by PTX. The Smad2, ERK1/2 and P38HOG pathways were activated in response to TGF-ß. However, TGF-ß displayed no activation of the JNK pathway in HPMC. Addition of PD98059 and SB203580, which blocked activation of ERK1/2 and p38HOG MAPK respectively, suppressed TGF-ß-induced collagen α1(I) mRNA expression. At concentration (17 μg/ml) that inhibited collagen gene expression, PTX suppressed ERK1/2 and p38HOG MAPK activation by TGF-ß. PTX had no effect on TGF-ß-induced activation of Smad2, under the same concentration. Conclusion. PTX inhibits TGF-ß-induced collagen gene expression in HPMC through modulations of the ERK1/2 and p38HOG MAPK pathways. Our study of PTX may provide therapeutic basis for clinical applications in prevention of EPS.

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