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 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.
Wei
X Q
XQ
Department of Immunology, University of Glasgow, United Kingdom.
Leung
B P
BP
Niedbala
W
W
Piedrafita
D
D
Feng
G J
GJ
Sweet
M
M
Dobbie
L
L
Smith
A J
AJ
Liew
F Y
FY
D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004198:Disease Susceptibility; D005260:Female; D007111:Immunity, Cellular / Q000235:genetics*; D020382:Interleukin-18 / Q000172:deficiency* / Q000235:genetics*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D018805:Sepsis / Q000235:genetics / Q000276:immunology; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*
D020382:Interleukin-18