Altered Immune Responses and Susceptibility to Leishmania major and Staphylococcus aureus Infection in IL-18-Deficient Mice

作者：Xiaoqing Wei, Bernard P. L. Leung, Wanda Niedbała, David M. Piedrafita, Gui-Jie Feng, Matt Sweet, Lorraine Dobbie, Andrew J. Smith, Foo Yew Liew · 发表于：The Journal of Immunology · 年份：1999 · DOI：10.4049/jimmunol.163.5.2821 · 被引用次数：179 · 研究领域：Research on Leishmaniasis Studies、Toxin Mechanisms and Immunotoxins、Autoimmune and Inflammatory Disorders Research

IL-18, formerly designated IFN-inducing factor, is a novel cytokine produced by activated macrophages. It synergizes with IL-12 in the induction of the development of Th1 cells and NK cells. To define the biological role of IL-18 in vivo, we have constructed a strain of mice lacking IL-18. Homozygous IL-18 knockout (-/-) mice are viable, fertile, and without evident histopathologic abnormalities. However, in contrast to the heterozygous (+/-) or wild-type (+/+) mice, which are highly resistant to the infection of the protozoan parasite Leishmania major, the IL-18-/- mice are uniformly susceptible. The infected IL-18-/- mice produced significantly lower levels of IFN-gamma and larger amounts of IL-4 compared with similarly infected +/- and +/+ mice. In contrast, when infected with the extracellular Gram-positive bacteria Staphylococcus aureus, the IL-18-/- mice developed markedly less septicemia than similarly infected wild-type (+/+) mice. However, the mutant mice developed significantly more severe septic arthritis than the control wild-type mice. This was accompanied by a reduction in the levels of Ag-induced splenic T cell proliferation, decreased IFN-gamma and TNF-alpha synthesis, but increased IL-4 production by the mutant mice compared with the wild-type mice. These results therefore provide direct evidence that IL-18 is not only essential for the host defense against intracellular infection, but it also plays a critical role in regulating the synthesis of inflammatory ...