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 int racellular signal transduction via the T cell receptor that in turn leads t o either TH1, or TH2, -type responses to antigen. This choice of response i nvolves differential phosphorylation of STATS (Signal Transducers and Activ ators of Transcription) for induction of STAT activity. Interferon-gamma ac tivates STAT1, a TH1-type mediator, and interleukin-4 activates STAT6, a TH 2-type mediator. We ask if FK506 biases STAT activation toward a TH2-type r esponse. Methods. Cells of the RAW 264.7 mouse macrophage line were treated with int erleukin-4, or interferon-gamma, plus or minus FK506, and any effect on STA T6 and STAT1 was compared. Results, Interleukin-C specifically induced activation of STAT6, and pretre atment with FK506 enhanced this activity. Interferon-gamma induced STAT1 ac tivity but this was not influenced by FK506 pretreatment. Conclusion. FK506 protects against allograft rejection by inhibiting interl eukin-a production, Such protection may be enhanced by FK506-mediated up-re gulation of STAT6 activity.