Stabilization of IFN-γ mRNA by MAPK p38 in IL-12- and IL-18-stimulated human NK cells

The rapid induction of interferon-γ (IFN-γ) by innate cytokines such as interleukin 12 (IL-12) and IL-18 is critical for immunity against infectious pathogens. We investigated the molecular mechanisms underlying this response. IL-12 and IL-18 rapidly and synergistically induced the secretion of IFN-γ by freshly purified human peripheral blood lymphocytes. At early time points, IFN-γ was expressed almost exclusively by natural killer cells and in both CD56^brlght and CD56^dlm subpopulations. Mitogen-activated protein kinase p38 was activated strongly by IL-18 and weakly by IL-12 in natural killer cells but was not activated by either cytokine in T cells. The expression of IFN-γ mRNA and protein was dose-dependently blocked by SB203580, a specific inhibitor of mitogen-activated protein kinase p38, which also caused a dramatic destabilization of IFN-γ mRNA. The 3′ untranslated region (UTR) of IFN-γ mRNA conferred p38 responsiveness to a heterologous reporter mRNA. Therefore, the synergistic induction of IFN-γ by IL-12 and IL-18 in natural killer cells is mediated at least in part by p38-dependent and 3′ UTR-mediated stabilization of IFN-γ mRNA.