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STAT 6 up-regulation by FK506 in the presence of interleukin-4
S D Moffatt1, M Cockman, S M Metcalfe
1Department of Surgery, University of Cambridge, Addenbrooke's Hospital, UK.
Background:
FK506 perturbs normal phosphorylation by inhibition of the PP2B protein phosphatase, calcineurin. Calcineurin activity is required for intracellular signal transduction via the T cell receptor that in turn leads to either TH1, or TH2, -type responses to antigen. This choice of response involves differential phosphorylation of STATS (Signal Transducers and Activators of Transcription) for induction of STAT activity. Interferon-gamma activates STAT1, a TH1-type mediator, and interleukin-4 activates STAT6, a TH2-type mediator. We ask if FK506 biases STAT activation toward a TH2-type response.
Methods:
Cells of the RAW 264.7 mouse macrophage line were treated with interleukin-4, or interferon-gamma, plus or minus FK506, and any effect on STAT6 and STAT1 was compared.
Results:
Interleukin-4 specifically induced activation of STAT6, and pretreatment with FK506 enhanced this activity. Interferon-y induced STAT1 activity but this was not influenced by FK506 pretreatment.
Conclusion:
FK506 protects against allograft rejection by inhibiting interleukin-2 production. Such protection may be enhanced by FK506-mediated up-regulation of STAT6 activity.