Inhibition of alanyl-aminopeptidase on CD4+CD25+ regulatory T-cells enhances expression of FoxP3 and TGF-beta1 and ameliorates acute colitis in mice.
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.
Bank
Ute
U
IMTM GmbH, D-39120 Magdeburg, Germany.
Tadje
Janine
J
Täger
Michael
M
Wolke
Carmen
C
Bukowska
Alicja
A
Ittenson
Annelore
A
Reinhold
Dirk
D
Helmuth
Martin
M
Ansorge
Siegfried
S
Shakespeare
Ann
A
Vieth
Michael
M
Malfertheiner
Peter
P
Naumann
Michael
M
Lendeckel
Uwe
U
D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D015704:CD4 Antigens / Q000378:metabolism*; D003092:Colitis / Q000201:enzymology* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism