Function of NFAT inhibitor

2018-09-24

Introduction 

NFAT, the nuclear factor of activated T cells, is a family of transcription factors that play an important role in inducing gene transcription in immune response. NFAT was firstly found inside T cells for the transcription of interleukin-2 (IL-2). It can also be expressed in many immune cells, such as B lymphocytes, mast cells, eosinophils and so on. Its activity is regulated by calcium dependent calcineurin. NFAT inhibitor could regulate NFAT pathway for selective immunosuppressive and anti-inflammatory responses.

Pharmacologic action

The NFAT activation process can be described as multiple steps: intracellular calcium mobilization, calcineurin-mediated dephosphorylation, import of NFAT to the nucleus, target gene binding in the nucleus. Each of the steps can be a point of inhibitors that suppresses NFAT function. Due to its essential role in the activation of T cells, NFAT signaling is an important pharmacological target for the induction of immunosuppression, limiting the adverse effects in transplantation.

Functions

NFAT belongs to a family of transcription factors that are involved in the regulation of transcription of pro-inflammatory genes, such as IL-2. The NFAT inhibitors, such as cyclosporine (CsA) and tacrolimus (FK-506), can inhibit calcineurin-mediated dephosphorylation of NFAT, interfere with this signaling pathway and prevent the activation of NFAT. They have the potential to regulate immunosuppressive and anti-inflammatory responses. Studies have shown that NFAT inhibitors could be used in organ transplantation and many chronic diseases, such as bronchial asthma, Alzheimer's disease, inflammatory bowel disease, diabetes, osteoporosis, osteoarthritis, myocarditis, and so on.

Pharmacokinetics and metabolism

NFAT inhibitors are metabolized and degraded by liver and excreted out of the body through kidney. Toxicity is associated with NFAT inhibitors because they inhibit the side effects of calcineurin in non-immune cells, which induces kidney injure. It limits their use when immunosuppressing drug therapy is required, including allergy and inflammation.

References:

1. Shaw, J. P., Utz, P. J., Durand, D. B., Toole, J. J., Emmel, E. A., & Crabtree, G. R. (1988). Identification of a putative regulator of early T cell activation genes. Science, 241(4862), 202-205.

2. Venkatesh, N., Feng, Y., DeDecker, B., Yacono, P., Golan, D., Mitchison, T., & McKeon, F. (2004). Chemical genetics to identify NFAT inhibitors: potential of targeting calcium mobilization in immunosuppression. Proceedings of the National Academy of Sciences, 101(24), 8969-8974.

3. Lee, M., & Park, J. (2006). Regulation of NFAT activation: a potential therapeutic target for immunosuppression. Molecules & Cells (Springer Science & Business Media BV), 22(1).

4. Rao, A., Luo, C., & Hogan, P. G. (1997). Transcription factors of the NFAT family: regulation and function. Annual review of immunology, 15(1), 707-747.

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