Critical involvement of IL-12 in IFN-gamma induction by calcineurin antagonists in activated human lymphocytes

Journal of Leukocyte Biology
Miriam WittmannThomas Werfel

Abstract

Calcineurin antagonists are known as potent immunosuppressants working particularly on T cells by virtue of their capacity to block nuclear factor of activated T cell (NFAT) activation and translocation to the nucleus. In addition to interleukin (IL)-2 suppression, T helper cell type 1 (Th1) as well as Th2 cytokine transcription is blocked by calcineurin antagonists. Here, we show that calcineurin antagonists such as cyclosporin A (CsA) or tacrolimus can markedly enhance the production of interferon-gamma (IFN-gamma) by human T cells. This increased IFN-gamma production is dependent on T cell receptor (TCR) and CD28 signaling as well as on the presence of IL-12. IL-27, which could mimic the effect of IL-12, was however less potent in inducing IFN-gamma production in the presence of CsA and TCR stimulation. Other cytokines such as IL-23, IL-18, IL-2, or the Th2-related cytokine IL-4 are not able to support a calcineurin antagonist-dependent up-regulation of IFN-gamma. CsA-dependent IFN-gamma production is observable in therapeutic concentrations. The effect is independent of IL-10 or IL-4, as addition of these cytokines could not inhibit the CsA-induced IFN-gamma production. The effect of calcineurin antagonists is associated wi...Continue Reading

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