IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production

Interleukin-12 (IL-12) and IL-18 induce synergistic transcription of interf eron gamma (IFN-gamma) that is T cell receptor (TCR)-independent, not inhib ited by cyclosporin A and requires new protein synthesis. To characterize t his pathway, we screened for genes that are induced in IL-12- and IL-18-tre ated T helper type I cells. GADD45 beta, which activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase kinase 4 (MEKK4 ), was induced by IL-18 and augmented by IL-12, GADD45 beta expression in n aive CD4(+)T cells activated p38 MAPK and selectively increased cytokine-in duced, but not TCR-induced, IFN-gamma production. Kinase-inactive MEKK4 and inhibition of the p38 MAPK pathway both selectively inhibit cytokine-induc ed, but not BCR-induced, IFN-gamma production. Thus, the synergy between IL -12 and IL-18 may involve GADD45 beta induction, which can maintain the MEK K4 and p38 MAPK activation that is necessary for cytokine-induced, but not TCR-induced, IFN-gamma production.