Interleukin-18 Induces Interferon-γ Production through NF-κB and NFAT Activation in Murine T Helper Type 1 Cells

Interleukin-18 (IL-18) combined with anti-CD3 monoclonal antibody (mAb) induced interferon-γ (IFN-γ) production by T helper type 1 (Th1) cells. Neither IL-18 nor anti-CD3 mAb alone induced production of IFN-γ. Although treatment with IL-18 alone induced full activation of NF-κB in Th1 cells, it was not sufficient for the production of IFN-γ. To examine the importance of NF-κB activation in IFN-γ production, we established Th1 cells which expressed a transdominant IκBα mutant. In these cells, activation of NF-κB and production of IFN-γ by IL-18 were suppressed. On the other hand, we examined the T cell receptor (TCR)/CD3-mediated signaling pathway. FK506, an inhibitor of NFAT activation, inhibited IFN-γ production by IL-18 without any effect on the NF-κB activation. We conclude that dual signaling consisting of IL-18-induced NF-κB activation and TCR/CD3-mediated NFAT activation is crucial for IFN-γ production by IL-18 in murine Th1 cells.