IL-12 synergizes with IL-18 or IL-1 beta for IFN-gamma production from human T cells

IL-18 is a proinflammatory cytokine that plays an important role in NK cell activation and T(h)1 response. IL-18 has a structural homology to IL-1, pa rticularly IL-1 beta. IL-18R, composed of IL-1R-related protein (IL-18R alp ha) and IL-1R accessory protein-like (IL-18R beta), belongs to the IL-1R fa mily. Furthermore, IL-18R at least partly shares the signal transducing sys tem 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 investi gate whether, like IL-18, IL-1 beta synergizes with IL-12 in inducing IFN-g amma production from human T cells and plays an important role in the T(h)1 response. Here we show that IL-12 and IL-1 beta synergistically induce T c ells to proliferate and produce IFN-gamma without their TCR engagement. IL- 12 stimulation induced an increase in the proportion of T cells positive fo r IL-18R, Then, IL-12-stimulated T cells responded to IL-18 or IL-1 beta by their proliferation and IFN-gamma production, although levels of IL-1 beta -induced responses were lower, CD4(+)CD45RA(+) T cells, although they const itutively expressed IL-18R beta mRNA, did not express IL-18R alpha mRNA, Ph ytohemagglutinin (PHA) stimulation alone induced IL-18R alpha mRNA without affecting the expression of IL-18R beta mRNA, T(h)1-inducing conditions (PH A, IL-12 and anti-IL-4) further increased this expression. We also show tha t T(h)1 cells but not T(h)2 cells have increased expression of IL-18R and I L-1R, and produce IFN-gamma in response to IL-18 and/or IL-1 beta.