The Phosphodiesterase Inhibitor, Pentoxifylline, Alters Rat Intestinal Epithelial Cell Proliferation via Changes in the Expression of Transforming Growth Factors

Abstract

Background: Phosphodiesterase (PDE) inhibitors, among which pentoxifylline (PTX), are candidate molecules for the treatment of TNF- α -dependent inflammatory diseases. Based on the controversial effects of PTX observed in experimentally-induced colitis, the aim of this work was to analyse its influence on intestinal epithelial cell proliferation and growth factor expression using the well-established IEC18 cell line. Methods : The effects of PTX, and of an activation (addition of dibutyryl-cAMP, db-cAMP) or inhibition (by a specific cAMP-protein kinase inhibitor, PKI) of the cAMP pathway, were examined after 3 days of culture. The IEC18 cell proliferation and [ 3 H] thymidine incorporation, as well as the expression of TGF- α , TGF- β 1 and- β 2 mRNAs, were analysed in basal culture conditions and in the presence of the pro-inflammatory cytokine, TNF- α. Results : PTX, like exogenous db-cAMP, inhibited in a dose-dependent manner the basal and TNF- α -modulated IEC18 cell proliferation; this effect was partly prevented by PKI. We confirmed that PTX induced a dose-related increase in intracellular cAMP. Concomitantly, the expression of TGF- α mRNA dropped and that of TGF- β 2 increased. Addition of db-cAMP instead of PTX also decreased TGF- α mRNA, but did not change TGF- β 2 transcripts. The decrease in the expression of TGF- α mRNA caused by PTX and db-cAMP was completely abolished by PKI; in contrast, TGF- β 2 remained unaltered. Yet, anti-TGF- β 2 antibodies partially restored the PTX-inhibited cell proliferation. Conclusion: The phosphodiesterase inhibitor, PTX, inhibits IEC18 cell proliferation via a differential modulation of TGF- α and TGF- β 2 expression. The drop in TGF- α mRNA is related to increasing intracellular cAMP, whereas the effect upon TGF- β 2 appears cAMP-independent.

• Camp
• Intestinal Epithelial Cell Line
• Pentoxifylline
• Phosphodiesterase Inhibitor
• Proliferation
• Protein Kinase A
• Tgf-ALPHA
• Tgf-BETA