Critical involvement of IL‐12 in IFN‐γ induction by calcineurin antagonists in activated human lymphocytes

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‐γ (IFN‐γ) by human T cells. This increased IFN‐γ 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‐γ 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‐γ. CsA‐dependent IFN‐γ 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‐γ production. The effect of calcineurin antagonists is associated with an increased c‐fos expression and DNA‐binding activity of the transcription factor activated protein‐1 but not with increased DNA‐binding activity of T‐bet. Our study further supports the relevance of known calcineurin activities other than NFAT activation. The presented data may help to explain why concomitant infections (resulting in increased IL‐12 expression) under therapy with calcineurin antagonists often have a negative impact on the activity of the underlying disease (e.g., autoimmune disease).