A critical role for interleukin 18 in primary and memory effector responses to Listeria monocytogenes that extends beyond its effects on interferon gamma production

The stimulation of interferon (IFN)-gamma by interleukin (IL)-12 has been s hown to provide protection from intracellular pathogens such as Listeria mo nocytogenes. Tumor necrosis factor (TNF) is also a major player in the reso lution of Listeria infections and is suggested to have more global effects than can be explained by the induction of IFN-gamma alone. Since IL-18 syne rgizes with IL-12 to induce IFN-gamma production by natural killer and T he lper (Th)1 cells, we determined its role in responses to Listeria. IL-18 ap peared to be even more potent than either IL-12 or IFN-gamma for protection against this pathogen and IL-18 enhanced bacterial clearance in the comple te absence of IFN-gamma. Indeed IL-18 was comparable to TNF in its ability to resolve the infection and showed a lowered protective capacity in the ab sence of TNF. Moreover, IL-18 induced macrophages to secrete both TNF and n itric oxide after a Listeria infection. IL-18 was also essential for optima l IFN-gamma production by antigen-specific T cells. Therefore, IL-18 operat es via its effects on both the innate immune response, including macrophage s, as well as on Th1 cells, to protect against Listeria.