Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|The Adverse Outcome Pathway on binding of FK506-binding protein 12 (FKBP12) by calcineurin inhibitors leading to immunosuppression||KE|
Level of Biological Organization
How this Key Event works
Effects on T cell
NFAT/AP-1 complex might bind to the promoter or enhancer regions of the cytokine genes in T cells; therefore, productions of IL-2, IL-3, IL-4, IL-5, GM-CSF and other T-cell-derived cytokines after activation of T cells were reported to be suppressed by FK506 treatment in vitro and in vivo as the result of hindered nuclear translocation of NFAT. FK506 inhibited both IL-2 and IFN-γ mRNA expression in anti-CD3/PMA-activated cells. FK506 had suppressed the expression of IL-4 mRNA in the presence of either anti-CD3or PMA-activated cells after 5h of culture (Dumont et al. 1998).
Effects on B cell
In B-cells, stimulus passes through the B-cell receptor (BCR), increasing the concentration of calcium in the B-cell, leading to NFAT nuclear localization in the same manner as T-cells (Bhattacharyya et al.2011). Inhibition of calcineurin phosphatase activation by FK506 suppresses induction of TNF-α following anti-Ig or anti-CD40 antibody stimulation (Goldfeld et al. 1992, Goldfeld et al. 1994, Boussiotis et al. 1994).
Effects on dendritic cells
FK506 suppresses expression of IL-2R (CD25) and costimulatory molecules CD80 (B7.1)/CD40 in Langerhans cells.
Effects on natural killer (NK) cells and NKT cells
In human NK cells, FK506 suppresses IL-2 responsive proliferation and cytokine production as well as lowers cytotoxicity directed toward K562 tumor cells (Kim et al. 2010). FK506 suppresses IL-2 production of NKT cell line DN32.D3 induced by stimulus from phorbol 12-myristate 13-acetate (PMA)/calcium-ionophore (van Dieren et al. 2010).
How it is Measured or Detected
Suppression of mRNA levels of cytokines can be measured by RNase protection assay in vitro and ex vivo. Inhibition of IL-2, IL-3, IL-4, IL-5, GM-CSF, IFN-γ, TNF-α production and secretion are measurable by sandwich ELISA.
Evidence Supporting Taxonomic Applicability
In human peripheral blood mononuclear cells (PBMC), FK506 suppresses T-cell activation–induced production of IL-1β and TNF-α (Sakuma et al. 2000). It also suppresses production of cytokines such as IL-2, IL-3, IL-4, IL-5, IFN-γ, and GM-CSF, which is induced by CD2/CD3 or CD3/CD26 stimulation, at least as if not more strongly than steroids in human PBMC (Sakuma et al. 2001a). Moreover, it suppresses production of IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, and GM-CSF, which is induced by CD3/PMA stimulation in human PBMC (Dumont et al. 1998).
 Bhattacharyya, S., Deb, J., Patra, A.K., Thuy Pham, D.A., Chen, W., Vaeth, M., Berberich-Siebelt, F., Klein-Hessling, S., Lamperti, E.D., Reifenberg, K., Jellusova, J., Schweizer, A., Nitschke, L., Leich, E., Rosenwald, A., Brunner, C., Engelmann, S., Bommhardt, U., Avots, A., Müller, M.R., Kondo, E. and Serfling, E. (2011). NFATc1 affects mouse splenic B cell function by controlling the calcineurin-NFAT signaling network. The Journal of experimental medicine 208 (4): 823-39.
 Boussiotis, V.A., Nadler, L.M., Strominger, J.L. and Goldfeld, A.E. (1994). Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells. Proceedings of the National Academy of Sciences of the United States of America 91 (15): 7007-11.
 Dumont, F.J., Staruch, M.J., Fischer, P., DaSilva, C. and Camacho, R. (1998). Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. Journal of immunology 160 (6): 2579-89.
 Flanagan, W.M., Corthésy, B., Bram, R.J. and Crabtree, G.R. (1991). Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352 (6338): 803-7.
 Goldfeld, A.E., Flemington, E.K., Boussiotis, V.A., Theodos, C.M., Titus, R.G., Strominger, J.L. and Speck, S.H. (1992). Transcription of the tumor necrosis factor alpha gene is rapidly induced by anti-immunoglobulin and blocked by cyclosporin A and FK506 in human B cells. Proceedings of the National Academy of Sciences of the United States of America 89 (24): 12198-201. ,
 Goldfeld, A. E., Tsai, E., Kincaid, R., Belshaw, P. J., Schrieber, S. L., Strominger, J. L. and Rao, A. (1994). Calcineurin mediates human tumor necrosis factor alpha gene induction in stimulated T and B cells. Journal of experimental medicine. 180(2): 763-768.
 Imai, A., Sahara, H., Tamura, Y., Jimbow, K., Saito, T., Ezoe, K., Yotsuyanagi, T. and Sato, N. (2007). Inhibition of endogenous MHC class II-restricted antigen presentation by tacrolimus (FK506) via FKBP51. European journal of immunology. 37(7): 1730-1738.
 Jain, J., McCaffrey, P. G., Valge-Archer, V. E. and Rao, A. (1992). Nuclear factor of activated T cells contains Fos and Jun. Nature. 356(6372): 801-804.
 Jain, J., Miner, Z. and Rao, A. (1993). Analysis of the preexisting and nuclear forms of nuclear factor of activated T cells. Journal of immunology. 151(2): 837-848.Kim, T., Kim, N. and Kang, H. J. (2010). FK506 causes cellular and functional defects in human natural killer cells. Journal of leukocyte biology. 88:1089-1097.
 Lee, Y. R., Yang, I. H., Lee, Y. H., Im, S. A., Song, S., Li, H., Han, K., Kim, K., Eo, S. K. and Lee, C. K. (2005). Cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC-restricted antigen presentation pathways in dendritic cells. Blood. 105(10): 3951-3955.
 Rao, A., Luo, C., and Hogan, PG. (1997). Transcription factors of the NFAT family: regulation and function. Annual Review of Immunology 15: 707-47.
 Sakuma, S., Kato, Y., Nishigaki, F., Sasakawa, T., Magari, K., Miyata, S., Ohkubo, Y., and Goto, T. (2000). FK506 potently inhibits T cell activation induced TNF-α and IL-1β production in vitro by human peripheral blood mononuclear cells. British Journal of Pharmacology 130(7): 1655-63.
 Sakuma, S., Higashi, Y., Sato, N., Sasakawa, T., Sengoku, T., Ohkubo, Y., Amaya, T., and Goto, T. (2001a). Tacrolimus suppressed the production of cytokines involved in atopic dermatitis by direct stimulation of human PBMC system. (Comparison with steroids). International Immunopharmacology 1(6): 1219-26.
 Sasakawa, Y., Sakuma, S., Higashi, Y., Sasakawa, T., Amaya, T., and Goto, T. (2000). FK506 suppresses neutrophil chemoattractant production by peripheral blood mononuclear cells. European Journal of Pharmacology 403(3): 281-8.
 Schreiber, SL., and Crabtree, GR. (1992). The mechanism of action of cyclosporin A and FK506. Immunology Today 13(4): 136-42.
 van Dieren, J.M., Lambers, M.E.H., Kuipers, E.J., Samsom, J.N., van der Woude, C.J. and Nieuwenhuis, E.E.S. (2010). Local immune regulation of mucosal inflammation by tacrolimus. Digestive diseases and sciences 55(9): 2514-19.