title: 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-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM U381, Strasbourg, France.
authors.forename: M
authors.initials: M
authors.lastname: Diab-Assef
authors.forename: J M
authors.initials: JM
authors.lastname: Reimund
authors.forename: J
authors.initials: J
authors.lastname: Ezenfis
authors.forename: B
authors.initials: B
authors.lastname: Duclos
authors.forename: M
authors.initials: M
authors.lastname: Kedinger
authors.forename: C
authors.initials: C
authors.lastname: Foltzer-Jourdainne
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D007413:Intestinal Mucosa / Q000166:cytology; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger; D051381:Rats; D015291:Transforming Growth Factors / Q000096:biosynthesis*
chemical_list: D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D003994:Bucladesine; D015291:Transforming Growth Factors; D000242:Cyclic AMP; D010431:Pentoxifylline