Interferon‐γ‐inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin‐12 for interferon‐γ production

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Abstract
The novel cytokine interferon‐γ‐inducing factor (IGIF) augments natural killer (NK) cell activity in cultures of human peripheral blood mononuclear cells (PBMC), similarly to the structurally unrelated cytokine interleukin (IL)‐12. IGIF has been found to enhance the production of interferon‐γ (IFN‐γ) and granulocyte/macrophage colony‐stimulating factor (GM‐CSF) while inhibiting the production of IL‐10 in concanavalin A (Con A)‐stimulated PBMC. In this study, when anti‐CD3 monoclonal antibody (mAb)‐stimulated human enriched T cells were exposed to IGIF, the cytokine dose‐dependently enhanced the proliferation of the cells and this could be completely inhibited by a neutralizing antibody against IL‐2 at lower concentrations of IGIF. Neutralizing antibody against IFN‐γ had only insignificant inhibitory effects on T cell proliferation at higher concentrations of IGIF. Enzyme‐linked immunosorbent assays (ELISA) revealed that, like PBMC, T cells exposed to IGIF produced large amounts of IFN‐γ; however, changes in the production of IL‐4 and IL‐10 were minimal. IGIF, but not IL‐12, significantly enhanced IL‐2 and GM‐CSF production in T cell cultures, as determined by CTLL‐2 bioassay and ELISA, respectively; however, both IGIF and IL‐12 enhanced IFN‐γ production by the T cells. When T cells were exposed to a combination of IGIF and IL‐12, a synergistic effect was observed on the production of IFN‐γ, but not on production of IL‐2 and GM‐CSF. In conclusion, IGIF enhances T cell proliferation apparently through an IL‐2‐dependent pathway and enhances Th1 cytokine production in vitro and exhibits synergism when combined with IL‐12 in terms of enhanced IFN‐γ production but not IL‐2 and GM‐CSF production. Based on structural and functional differences from any known cytokines, it was recently proposed that this cytokine be designated interleukin‐18.