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

TitleAltered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice.
Publication TypeJournal Article
Year of Publication1999
AuthorsWei XQ, Leung BP, Niedbala W, Piedrafita D, Feng GJ, Sweet M, Dobbie L, Smith AG, Liew FY
JournalJ Immunol
Date Published1999 Sep 1
KeywordsAnimals, Arthritis, Cells, Cultured, Crosses, Genetic, Disease Susceptibility, Female, Immunity, Cellular, Interleukin-18, Leishmania major, Leishmaniasis, Cutaneous, Lymphocyte Activation, Mice, Mice, Inbred NZB, Mice, Knockout, Sepsis, Staphylococcal Infections, Staphylococcus aureus

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 cytokines, and therefore could be an important target for therapeutic intervention.

Alternate JournalJ. Immunol.
PubMed ID10453027
Grant List / / Wellcome Trust / United Kingdom