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

Author： Diab-Assef M. Reimund J. M. Ezenfis J. Duclos B. Kedinger M. Foltzer-Jourdainne C.

Publisher： Informa Healthcare

ISSN： 0036-5521

Source： Scandinavian Journal of Gastroenterology, Vol.37, Iss.2, 2002-02, pp. : 206-214

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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 [³H] thymidine incorporation, as well as the expression of TGF-α, TGF-β1 and-β2 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-β2 increased. Addition of db-cAMP instead of PTX also decreased TGF-αmRNA, but did not change TGF-β2 transcripts. The decrease in the expression of TGF-α mRNA caused by PTX and db-cAMP was completely abolished by PKI; in contrast, TGF-β2 remained unaltered. Yet, anti-TGF-β2 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-β2 expression. The drop in TGF-α mRNA is related to increasing intracellular cAMP, whereas the effect upon TGF-β2 appears cAMP-independent.