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Published online before print April 26, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0605328

Received for publication June 18, 2005.
Revised February 15, 2006.
Accepted for publication March 6, 2006.

Article

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

Department of Dermatology and Allergology, Hannover Medical School, Germany

	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- (IFN-) by human T cells. This increased IFN- 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- 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-. CsA-dependent IFN- 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- 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).

Key Words: T cells • cytokines • cell activation • signal transduction

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