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Inhibition of alanyl-aminopeptidase on CD4+CD25+ regulatory T-cells enhances expression of FoxP3 and TGF-beta1 and ameliorates acute colitis in mice.

Abstract
Inhibitors of alanyl-aminopeptidase e.g. phebestin increase the expression of transforming growth factor (TGF)-beta1 in mononuclear cells. We investigated whether phebestin also produced this effect in CD4+CD25+ T-cells and whether phebestin-treated CD4+CD25+ T-cells were capable of ameliorating acute colitis in mice. The suppressive activity of mouse CD4+CD25+ T-cells was assessed in vitro by co-culture with splenocytes. mRNA expression associated with the suppressive phenotype was determined in vitro and in vivo. The in vivo role of phebestin-exposed CD4+CD25+ T-cells was studied in sodium dextran sulfate-induced acute colitis in mice. The proliferation of activated effector T-cells or splenocytes in vitro was inversely correlated with the number of CD4+CD25+ T-cells. Phebestin pre-treatment substantially enhanced the suppressive activity of these cells and increased expression levels of TGF-beta1 and FoxP3. Furthermore, transfer of CD4+CD25+ T-cells exposed to phebestin for a short time ex vivo significantly reduced the mouse colitis disease activity index. We conclude that aminopeptidase inhibitors support the suppressive activity as well as TGF-beta1 and FoxP3 expression of natural regulatory T-cells.
AuthorsUte Bank, Janine Tadje, Michael Täger, Carmen Wolke, Alicja Bukowska, Annelore Ittenson, Dirk Reinhold, Martin Helmuth, Siegfried Ansorge, Ann Shakespeare, Michael Vieth, Peter Malfertheiner, Michael Naumann, Uwe Lendeckel
JournalInternational journal of molecular medicine (Int J Mol Med) Vol. 20 Issue 4 Pg. 483-92 (Oct 2007) ISSN: 1107-3756 [Print] Greece
PMID17786278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CD4 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Oligopeptides
  • RNA, Messenger
  • Transforming Growth Factor beta1
  • phebestin
  • CD13 Antigens
Topics
  • Animals
  • CD13 Antigens (antagonists & inhibitors)
  • CD4 Antigens (metabolism)
  • Colitis (enzymology, pathology)
  • Female
  • Forkhead Transcription Factors (genetics, metabolism)
  • Gene Expression Regulation (drug effects)
  • Humans
  • Immune Tolerance (drug effects)
  • Interleukin-2 Receptor alpha Subunit (metabolism)
  • Lymphocyte Activation (drug effects)
  • Mice
  • Mice, Inbred BALB C
  • Oligopeptides (pharmacology)
  • Phenotype
  • RNA, Messenger (genetics, metabolism)
  • T-Lymphocytes, Regulatory (cytology, drug effects, enzymology)
  • Transforming Growth Factor beta1 (genetics, metabolism)

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