Calcineurin In Immunosuppression

Calcineurin plays a key role in immunosuppression. There has been an unequivocal demonstration over the past few years that the drugs cyclosporin A, FK506, and rapamycin achieve immune suppression by inhibiting the function of calcineurin. That calcineurin was the target of some of these immunosuppressants was established some years ago. O'Keefe et al. (1992) transfected the catalytic calcineurin A into cells and showed that this raises the IC50 inhibitory concentration of cyclosporin and FK506. Besides, Jurkat cells that overexpressed calcineurin were resistant to the action of cyclosporin and FK506 and showed enhanced gene transcription that depended on NF-AT and related transcription factors (Clipstone and Crabtree, 1992).

These immunosuppressant drugs interact with specific intracellular immunophi-lin receptors, which results in the formation of a drug-immunophilin complex that is capable of blocking the function of its target, which, in this instance, is calcineurin (J. Liu et al. 1991; Ho et al. 1996). When T cells are activated by mitogenic signals or by antigen binding, they proliferate and switch on the expression of cytokine genes. Antigen binding to the TCR produces a cascade of signalling events (Figure 19), which have been elucidated in some detail.

TCR-antigen complex

Immunosuppressants (Cyclosporin A, FK506, rapamycin)

Calcineurin

Dephosphorylation of NF-AT

Translocation of NF-AT to nucleus

Formation of NF-AT/AP1 complex

Transcription of target genes (e.g. IL-2, IFN-y, TNF-a)

FIGURE 19 The involvement of calcineurin in a key position in the TCR-signalling cascade. See text for details.

Calcineurin participates in this signalling cascade as a key enzyme. It is responsible for dephosphorylating the transcription factor called NF-AT and this factor then translocates to the nucleus. NF-AT1 contains a regulatory domain, which lies N-terminal to its DNA-binding region, that binds to calcineurin (C. Luo et al. 1996). In this way calcineurin seems to be targeted to NF-AT. The maintenance of NF-AT in the nucleus requires high and sustained levels, not transients, of calcium (Tim-merman et al. 1996), probably reflecting its continual calcineurin-dependent activation and translocation. The NF-AT proteins are expressed in many cell types of the immune system, and these constitute a family of proteins that possess this conserved regulatory domain involved in their binding to calcineurin. NF-AT proteins resemble the Rel family of proteins with respect to their ability to bind to the regulatory elements of certain genes coding for cytokines (Rao et al. 1997). In the nucleus, NF-AT forms a complex with the transcription complex AP1 (jun/fos). The AP1/NF-AT complex then initiates the transcription of a number of genes, such as genes coding for the lymphokine, IL-2, IFN-y, and TNF-a, among others. The inhibition of calcineurin by the immunosuppressants inhibits the dephosphorylation of NF-AT and thereby inhibits its translocation to the nucleus and all the downstream events. Batiuk et al. (1997) have fully correlated the effects of cyclosporin A with the various

FIGURE 20 The multiple functions of calcineurin, on the cell division cycle, in the modulation of cell shape, adhesion and motility, and in the regulation of gene transcription. Also indicated are its participation in the functioning of immunosuppressants and its possible association with abnormal phosphorylation of tau in Alzheimer's disease.

Cytoskeletal instability Abnormal tau/PHF formation

In Alzheimer's disease

FIGURE 20 The multiple functions of calcineurin, on the cell division cycle, in the modulation of cell shape, adhesion and motility, and in the regulation of gene transcription. Also indicated are its participation in the functioning of immunosuppressants and its possible association with abnormal phosphorylation of tau in Alzheimer's disease.

events of the cascade, namely the dephosphorylation of NF-AT, its translocation, binding of the transcription complex to the DNA, and the eventual activation of gene transcription. They also demonstrated the relationship between the extent of cal-cineurin inhibition, the inhibition of lymphocyte proliferation, and the degree of IFN-y production in vitro.

It would not be out of place to briefly mention here that calcineurin is involved in the autoimmune condition SLE. SLE affects women of child-bearing age. The menstrual cycle and pregnancy seem to affect disease activity (Lahita, 1993; Jungers et al. 1985; Mund et al. 1963). Rider et al. (1998) have shown that T cells from SLE patients respond to oestradiol by an up-regulation of calcineurin mRNA expression, in a dose-dependent fashion. The effect seems to be specific for oestradiol, because progesterone and dexamethasone fail to elicit a similar response. The increase in mRNA expression corresponds with calcineurin phosphatase activity in oestradiol-treated T-cell extracts. As Rider et al. (1998) pointed out, the mechanism by which oestrogen influences calcineurin expression is unclear, because the latter has no identifiable oestrogen response elements in its promoter region. However, they suggest that oestrogen could be exerting control at the level of calcineurin transcription. They cite the findings of H. Becker et al. (1995) that there is an increased NF-AT binding to IL-2 promoter in SLE patients as compared with control subjects. As discussed earlier in this section and shown in Figure 19, calcineurin plays a key role in the translocation of the NF-AT transcription factor to the nucleus. Therefore, it is conceivable that oestrogen influences the T-cell signal transduction cascade in SLE.

One is fully justified in concluding at the end of this chapter that calcineurin is a highly versatile phosphatase, and its functional repercussions, shown in Figure 20, are discernible in many facets of biological behaviour.

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