title: Calcineurin antagonists inhibit interferon-gamma production by downregulation of interleukin-18 in human mixed lymphocyte reactions.
abstract: Tacrolimus (FK-506) and cyclosporin A (CsA) are calcineurin antagonists used widely as T-cell immunosuppressants; however, their relative efficacy on the production of interleukin-18 (IL-18) remains undefined. We have examined the effects of FK-506 and CsA on the cytokine generation of human peripheral blood mononuclear cells (PBMCs) in mixed lymphocyte reaction (MLR) with lipopolysaccharide (LPS). We studied the levels of interleukin-18 (IL-18), IL-12, IL-10, IL-6, IL-2 and interferon-gamma (IFN-gamma) in the supernatant in allo-MLR by ELISA assay. Supernatant levels of IFN-gamma, IL-2, IL-6, IL-10 and IL-12 were detected 12 h after MLR and markedly increased thereafter. In contrast, production of IL-18 was detected at 12 h, reached a near maximum level at 24 h and decreased at 72 h. These results suggested that IFN-gamma production depended on IL-18, IL-12 and IL-2 in the early phase of MLR and depended mainly on IL-12 and IL-2 in the late phase. Both calcineurin antagonists inhibit the generation of IL-18, which plays a large role in allogeneic cell interactions, in macrophages and they also promote an equivalent down-regulation of T helper 1 (Th1) and Th2 responses in a concentration-dependent manner. About 90% of IFN-gamma production induced by MLR was inhibited by an anti-IL-18 antibody, showing that IL-18 can trigger IFN-gamma production in MLR. These results suggest that dual signaling consisting of antigen-driven nuclear factor of activated T cells (NFAT) activation and LPS-mediated NF-kappaB activation is crucial for IL-18 production in macrophages, and that IL-18 can trigger IFN-gamma production in T-cells by MLR.
authors.affiliation: Department of Surgery I, Okayama University Medical School, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kuinose
authors.forename: H
authors.initials: H
authors.lastname: Iwagaki
authors.forename: Y
authors.initials: Y
authors.lastname: Morimoto
authors.forename: H
authors.initials: H
authors.lastname: Kohka
authors.forename: K
authors.initials: K
authors.lastname: Kobashi
authors.forename: H
authors.initials: H
authors.lastname: Sadamori
authors.forename: M
authors.initials: M
authors.lastname: Inagaki
authors.forename: N
authors.initials: N
authors.lastname: Urushihara
authors.forename: T
authors.initials: T
authors.lastname: Yagi
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D015536:Down-Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000096:biosynthesis*; D007959:Lymphocyte Culture Test, Mixed; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D020382:Interleukin-18; D007371:Interferon-gamma; D016572:Cyclosporine; D016559:Tacrolimus