STAT 6 up-regulation by FK506 in the presence of interleukin-4.
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.


CONCLUSIONS
FK506 protects against allograft rejection by inhibiting interleukin-2 production. Such protection may be enhanced by FK506-mediated up-regulation of STAT6 activity.
Moffatt
S D
SD
Department of Surgery, University of Cambridge, Addenbrooke's Hospital, UK.
Cockman
M
M
Metcalfe
S M
SM
D000818:Animals; D002460:Cell Line; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D050800:STAT6 Transcription Factor; D016559:Tacrolimus / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation
D007166:Immunosuppressive Agents; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma; D016559:Tacrolimus