Cyclosporin A and FK-506: Immunosuppression, inhibition of transcription and the role of calcineurin

Summary

Antigen presentation induces lymphokine gene expression in T cells and an autocrine stimulatory pathway leading to cell growth and proliferation. Cyclosporin A (CsA) and FK-506, two potent, clinically relevant immunosuppressive compounds, function by preventing lymphokine production, particularly interleukin-2. These compounds act at the level of transcription by inhibiting the activation of a set of transcription factors that are required for initiation of lymphokine gene expression. Several of these factors have been the subject of intense scrutiny. Some, such as NF-AT (nuclear factor of activated T cells) are cell type specific, while others, such as NF-κB, are ubiquitously expressed. These factors do not share a common mechanism of activation, but calcineurin, a Ca2+-dependent phosphoprotein phosphatase plays a central role in the activation of each of them. Thus, not only are these immunosuppressive drugs clinically important, but they have served as unique probes of the signal transduction pathways that lead to activation of specific transcription factors involved in lymphokine gene expression.

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Abbreviations

ARRE-1:

antigen receptor response element 1

CD28-RE:

CD28-responsive element

CsA:

cyclosporin A

IL-2:

interleukin-2

OAP:

octamer-associated protein

Oct-1:

octamer transcription factor-1

PMA:

phorbol myristate acetate

PKC:

protein kinase C

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O'Keefe, S.J., O'Neill, E.A. Cyclosporin A and FK-506: Immunosuppression, inhibition of transcription and the role of calcineurin. Perspectives in Drug Discovery and Design 2, 85–102 (1994). https://doi.org/10.1007/BF02171738

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Key words

  • NF-AT
  • NF-κB
  • T cell
  • Ca2+
  • AP-1