Key Event Title
|Level of Biological Organization|
Key Event Components
|cytokine production involved in inflammatory response||NFAT activation molecule 1||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|All life stages||High|
Key Event Description
Activated nuclear factor of activated T cells (NFAT) that has localized to the nucleus binds cooperatively at the site of the Interleukin-2 (IL-2) promoter with activator protein-1 (AP-1), which is a heterodimer comprising a Fos and a Jun protein (Schreiber and Crabtree 1992, Jain et al. 1992), thereby inducing transcription of IL-2 (Jain et al. 1993). Interfered nuclear localization of NFAT, induced by FK506, hinders the formation of the functional NFAT/AP-1 complexes necessary to binding at the site of IL-2 promoters (Flanagan et al. 1991).
NFAT is known to bind cooperatively at the promoters of Interleukin-4 (IL-4) and other T-cell cytokines as well as that of IL-2 (Macian et al. 2005).
Treatment of activated T cells with FK506 at 100ng/mL (124nM) or CsA at 500ng/mL (416nM) for 2 hours hinders the formation of functional NFAT/AP-1 in the nucleus (Flanagan et al. 1991).
How It Is Measured or Detected
Reductions in NFAT/AP-1 complex formation can be detected using a gel shift assay to test nuclear extracts from either stimulated or unstimulated Ar-5 T cells with radio-labelled NFAT binding oligonucleotide from murine IL-2 promoter. Anti-Fos and anti-Jun antibodies are used to examine NFAT/AP-1 complex formation (Jain et al. 1992).
Domain of Applicability
CN-NFAT system functionality is common among mammalian species, including humans and rodents. It is also possible that FK506-induced interference with NFAT/AP-1 complex formation at the promoter site of the IL-2 gene is common among mammalian T cells, including those of humans and rodents (Flanagan et al. 1991).
Evidence for Perturbation by Stressor
- 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.
- 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.
- Macian, F. (2005). NFAT proteins: key regulators of T-cell development and function. Nature reviews. Immunology. 5(6): 472-84.
- Schreiber, SL., and Crabtree, GR. (1992). The mechanism of action of cyclosporin A and FK506. Immunology Today 13(4): 136-42.