IL-12 synergizes with IL-18 or IL-1β for IFN-γ production from human T cells

Abstract

IL-18 is a proinflammatory cytokine that plays an important role in NK cell activation and T_h1 response. IL-18 has a structural homology to IL-1, particularly IL-1β. IL-18R, composed of IL-1R-related protein (IL-18Rα) and IL-1R accessory protein-like (IL-18Rβ), belongs to the IL-1R family. Furthermore, IL-18R at least partly shares the signal transducing system with IL-1R. Thus, the IL-18–IL-18R system has a striking similarity to the IL-1–IL-1R system. For this reason, we regarded it important to investigate whether, like IL-18, IL-1β synergizes with IL-12 in inducing IFN-γ production from human T cells and plays an important role in the T_h1 response. Here we show that IL-12 and IL-1β synergistically induce T cells to proliferate and produce IFN-γ without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R. Then, IL-12-stimulated T cells responded to IL-18 or IL-1β by their proliferation and IFN-γ production, although levels of IL-1β-induced responses were lower. CD4⁺CD45RA⁺ T cells, although they constitutively expressed IL-18Rβ mRNA, did not express IL-18Rα mRNA. Phytohemagglutinin (PHA) stimulation alone induced IL-18Rα mRNA without affecting the expression of IL-18Rβ mRNA. T_h1-inducing conditions (PHA, IL-12 and anti-IL-4) further increased this expression. We also show that T_h1 cells but not T_h2 cells have increased expression of IL-18R and IL-1R, and produce IFN-γ in response to IL-18 and/or IL-1β.