Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice

IL-18, formerly designated IFN-inducing factor, is a novel cytokine produce d by activated macrophages. It synergizes with IL-12 in the induction of th e development of Th1 cells and NK cells. To define the biological role of I L-18 in vivo, we have constructed a strain of mice lacking IL-18, Homozygou s IL-18 knockout (-/-) mice are viable, fertile, and without evident histop athologic abnormalities. However, in contrast to the heterozygous (+/-) or wild-type (+/+) mice, which are highly resistant to the infection of the pr otozoan parasite Leishmania major, the IL-18(-/-) mice are uniformly suscep tible. The infected IL-18(-/-) mice produced significantly lower levels of IFN-gamma and larger amounts of IL-4 compared with similarly infected +/- a nd +/+ mice. In contrast, when infected with the extracellular Gram-positiv e bacteria Staphylococcus aureus, the IL-18(-/-) mice developed markedly le ss septicemia than similarly infected wild-type (+/+) mice. However, the mu tant mice developed significantly more severe septic arthritis than the con trol wild-type mice. This was accompanied by a reduction in the levels of A g-induced splenic T cell proliferation, decreased IFN-gamma and TNF-alpha s ynthesis, but increased IL-4 production by the mutant mice compared with th e wild-type mice. These results therefore provide direct evidence that IL-1 8 is not only essential for the host defense against intracellular infectio n, but it also plays a critical role in regulating the synthesis of inflamm atory cytokines, and therefore could be an important target for therapeutic intervention.