Event:979

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Event Title

Interference of NFAT complex formation at the site of nuclear cytokine promoters, Inhibition

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 Strong

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

Activated NFAT that has localized to the nucleus binds cooperatively at the site of the Interleukin-2 (IL-2) promoter with activator protein 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). FK506, by interfering with NFAT nuclear localization, hinders the formation of the functional NFAT complexes necessary to binding at the site of IL-2 promoters (Flanagan et al. 1991). NFAT also binds at the site of IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) promoters (Foletta et al. 1998). Additionally, NFAT binds cooperatively at the site of IL-2, IL-4, and TNF promoters as well as at the site of IL-3 and IL-4 enhancers with avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), early growth response 1 (EGR1), early growth response 4 (EGR4), interferon-regulatory factor 4 (IRF4), octamer-binding transcription factor (OCT), and other transcriptional partners to induce transcription of a variety of cytokines (Macian 2005).

How it is Measured or Detected

Inhibition of generation of NFAT/AP-1 complex can be detected by gel shift assay. Jain et al. (1992) conducted that nuclear extracts from unstimulated or stimulated Ar-5 T cells were applied to the gel shift assays with radio-labelled murine NFAT oligonucleotide. Suppression of mRNA levels of cytokines can be measured by RNase protection assay in vitro and ex vivo.

Evidence Supporting Taxonomic Applicability

FK506-induced interference with NFAT/AP-1 complex formation at the promoter site of the IL-2 gene might be in common among mammalian T cells including humans and rodents. Synthesis of IL-3, IL-4, IL-5 and GM-CSF by T cells might also be inhibited with FK506 by similar mechanisms as those of IL-2.

References

[1] Schreiber, SL., and Crabtree, GR. (1992). The mechanism of action of cyclosporin A and FK506. Immunology Today 13(4): 136-42.

[2] 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.

[3] 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.

[4] 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.

[5] Foletta, V.C., Segal, D.H. and Cohen, D.R. (1998). Transcriptional regulation in the immune system: all roads lead to AP-1. Journal of leukocyte biology 63 (2): 139-52.

[6] Macian, F. (2005). NFAT proteins: key regulators of T-cell development and function. Nature reviews. Immunology. 5(6): 472-84.

[7] Rao, A., Luo, C., and Hogan, PG. (1997). Transcription factors of the NFAT family: regulation and function. Annual Review of Immunology 15: 707-47.

[8] 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.