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*
Department of Immunology, University of Glasgow, Glasgow, United Kingdom; and
Gene Targeting Laboratory, Centre for Genome Research, University of Edinburgh, Edinburgh, United Kingdom
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-
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- and TNF-
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.
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