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The phosphodiesterase inhibitor, pentoxifylline, alters rat intestinal epithelial cell proliferation via changes in the expression of transforming growth factors.

Authors: Diab-Assef, M  Reimund, JM  Ezenfis, J  Duclos, B  Kedinger, M  Foltzer-Jourdainne, C 
Citation: Diab-Assef M, etal., Scand J Gastroenterol. 2002 Feb;37(2):206-14.
Pubmed: (View Article at PubMed) PMID:11843059

BACKGROUND: Phosphodiesterase (PDE) inhibitors, among which pentoxifylline (PTX), are candidate molecules for the treatment of TNF-alpha-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-alpha, TGF-beta1 and -beta2 mRNAs, were analysed in basal culture conditions and in the presence of the pro-inflammatory cytokine, TNF-alpha. RESULTS: PTX, like exogenous db-cAMP, inhibited in a dose-dependent manner the basal and TNF-alpha-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-alpha mRNA dropped and that of TGF-beta2 increased. Addition of db-cAMP instead of PTX also decreased TGF-alpha mRNA, but did not change TGF-beta2 transcripts. The decrease in the expression of TGF-alpha mRNA caused by PTX and db-cAMP was completely abolished by PKI; in contrast, TGF-beta2 remained unaltered. Yet, anti-TGF-beta2 antibodies partially restored the PTX-inhibited cell proliferation. CONCLUSION: The phosphodiesterase inhibitor, PTX, inhibits IEC18 cell proliferation via a differential modulation of TGF-alpha and TGF-beta2 expression. The drop in TGF-alpha mRNA is related to increasing intracellular cAMP, whereas the effect upon TGF-beta2 appears cAMP-independent.

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CRRD Object Information
CRRD ID: 2302112
Created: 2008-11-19
Species: All species
Last Modified: 2008-11-19
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.