Tacrolimus-induced apoptosis and its prevention by interleukins in mitogen-activated human peripheral-blood mononuclear cells.
The present study demonstrated that tacrolimus (FK506) induced apoptosis in mitogen-activated human PBMCs and that several interleukins (ILs) prevented the apoptosis. Mitogen-activated PBMCs obtained from healthy subjects treated with 1 ng/ml of FK506 exhibited a DNA-ladder structure in agarose-gel electrophoresis. Moreover, in quantitative analysis of fragmented DNA using cell death detection ELISA, 1 ng/ml of FK506 induced maximal apoptotic induction, whereas > 10 ng/ml of glucocorticoids (GCs) or cyclosporine (CsA) was required to achieve maximal induction of apoptosis in PBMCs. FK506-induced apoptosis was efficiently attenuated by co-addition of ILs including IL-1beta (2 ng/ml), IL-2 (5 ng/ml) and IL-4 (40 ng/ml) into culture. The results showed that FK506 induces apoptosis in mitogen-activated PBMCs at concentrations which exhibited sufficient suppression of PBMC-blastogenesis. The data also suggested that cytokine networks including those via IL-1beta and IL-4 in addition to IL-2 prevent FK506-induced apoptosis.
Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
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A
Horigome
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T
Hirano
K
K
Oka
D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007375:Interleukin-1 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008934:Mitogens; D016559:Tacrolimus / Q000633:toxicity*
D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007376:Interleukin-2; D008934:Mitogens; D015847:Interleukin-4; D016559:Tacrolimus