title: Critical involvement of IL-12 in IFN-gamma induction by calcineurin antagonists in activated human lymphocytes.
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 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).
authors.affiliation: Department of Dermatology and Allergology, Ricklinger Str. 5, D-30449 Hannover, Germany. Wittmann.Miriam@MH-Hannover.de
authors.forename: Miriam
authors.initials: M
authors.lastname: Wittmann
authors.forename: Claudia
authors.initials: C
authors.lastname: Killig
authors.forename: Manuela
authors.initials: M
authors.lastname: Bruder
authors.forename: Ralf
authors.initials: R
authors.lastname: Gutzmer
authors.forename: Thomas
authors.initials: T
authors.lastname: Werfel
mesh_terms: D018106:CD28 Antigens / Q000276:immunology; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects* / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D018106:CD28 Antigens; D065095:Calcineurin Inhibitors; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D007371:Interferon-gamma; D016572:Cyclosporine; D016559:Tacrolimus